No. 1, March 2010

Transcription

No. 1, March 2010

Serbian Journal of
Dermatology and Venereology
ISSN 1821-0902
UDC 616.5(497.11)
Volume 2, Number 1, March 2010
ORIGINAL STUDY
ALTERNATIVE TREATMENT
OF PSORIASIS
REVIEW ARTICLE
TREATMENT OF ACNE VULGARIS
CASE REPORT
MALIGNANT TRANSFORMATION
OF A CHRONIC LEG ULCER
HISTORY OF MEDICINE
HISTORY OF DERMATOVENEREOLOGY
IN SERBIA FROM 1919 – 1945: part 1
REPORT
FORTHCOMING EVENTS
Published by the
Serbian Association of Dermatovenereologists
SERBIAN ASSOCIATION OF DERMATOVENEREOLOGISTS
President of the Association
LJILJANA MEDENICA, Belgrade
SERBIAN JOURNAL OF DERMATOLOGY AND VENEREOLOGY
Editor-in-Chief
MARINA JOVANOVIĆ, Novi Sad
Assistants to the Editor-in-Chief
ZORAN GOLUŠIN, Novi Sad
DRAGAN JOVANOVIĆ, Niš
LIDIJA KANDOLF-SEKULOVIĆ, Belgrade
MILAN MATIĆ, Novi Sad
EDITORIAL BOARD
President
MILOŠ NIKOLIĆ, Belgrade
Secretary
DANIJELA DOBROSAVLJEVIĆ, Belgrade
Members
IVANA BINIĆ, Niš, Serbia
VERICA ĐURAN, Novi Sad, Serbia
ANNA GORKIEWICZ-PETKOW, Warsaw, Poland
CAMILA K. JANNIGER, New Jersey, USA
ĐORĐIJE KARADAGLIĆ, Belgrade, Serbia
ANDREAS KATSAMBAS, Athens, Greece
ALEKSANDAR KRUNIĆ, Chicago, USA
BOSILJKA LALEVIĆ-VASIĆ, Belgrade, Serbia
MARKO LENS, London, United Kingdom
JOHN McGRATH, London, United Kingdom
LJILJANA MEDENICA, Belgrade, Serbia
MILOŠ PAVLOVIĆ, Ljubljana, Slovenia
ROBERT A. SCHWARTZ, New Jersey, USA
MILENKO STANOJEVIĆ, Niš, Serbia
JACEK C. SZEPIETOWSKI, Wroclaw, Poland
GEORGE SORIN TIPLICA, Bucharest, Romania
NIKOLAI TSANKOV, Sofia, Bulgaria
NADA VUČKOVIĆ, Novi Sad, Serbia
RADOŠ ZEČEVIĆ, Belgrade, Serbia
Technical Assistant: Vesna Šaranović
English Proofreading: Marija Vučenović
Serbian Proofreading: Dragica Pantić
UDC Selection: Zorica Đokić
Reference Checking: Branislava Čikić
The Journal is published four times a year with the circulation of 300. Manuscripts are to be submitted to the
Editor-in-Chief: Prof. Dr. Marina Jovanović, Klinički centar Vojvodine,
Klinika za kożne i venerične bolesti, 21000 Novi Sad, Hajduk Veljkova 1-7
E-mail: [email protected], Tel: +381 21 484 3562; +381 21 451 781.
Copyright © 2009 by the Serbian Association of Dermatovenereologists
Published on behalf of The Serbian Association of Dermatovenereologists by Zlatni presek, Beograd
CONTENTS
Serbian Journal of Dermatology and Venereology 2010; 2 (1):1-40.
ORIGINAL STUDY
5
ALTERNATIVE TREATMENT OF PSORIASIS – IS RIFAMPICIN A MILD IMMUNOSUPRESSOR?
Ivan GROZDEV, Jana KAZANDJIEVA, Nikolai TSANKOV
REVIEW ARTICLE
13
TREATMENT OF ACNE VULGARIS: A LITERATURE REVIEW
Milica SUBOTIĆ and Verica ĐURAN
CASE REPORT
23
MALIGNANT TRANSFORMATION OF A CHRONIC LEG ULCER: A CASE REPORT
Kristina KOSTIĆ, Tomislav MLADENOVIĆ, Radoš ZEČEVIĆ
HISTORY OF MEDICINE
26
HISTORY OF DERMATOLOGY AND VENEREOLOGY IN SERBIA – PART IV/1: DERMATOVENEREOLOGY IN SERBIA FROM 1919 – 1945
Bosiljka M. LALEVIĆ-VASIĆ and Marina JOVANOVIĆ
REPORT
32
A REPORT ON THE 11TH INTERNATIONAL UNION AGAINST SEXUALLY TRANSMITTED INFECTIONS WORLD CONGRESS
Zoran GOLUŠIN
35
FORTHCOMING EVENTS
DERMATOLOGY AND VENEREOLOGY EVENTS 2009-2010
THE BELGRADE DERMATOVENEREOLOGIC MOULAGE COLLECTION
INSTITUTE OF DERMATOVENEREOLOGY, CLINICAL CENTER OF SERBIA, BELGRADE, SERBIA
ORIGINAL STUDY
Serbian Journal of Dermatology and Venereology 2010; 2 (1): 5-12
Alternative treatment of psoriasis - is rifampicin a mild
immunosupressor?
Ivan GROZEV, Jana KAZANDJEVA, Nikolai TSANKOV *
Department of Dermatology, Medical Faculty, Sofia
Tokuda Hospital, Sofia, Bulgaria
*Correspondence: Nikolai TSANKOV, E-mail: [email protected]
UDC 616.517-085
Abstract
Psoriasis is a common T-cell-mediated autoimmune inflammatory disease. Conventional systemic therapy includes:
methotrexate, cyclosporine, retinoids and psoralen ultraviolet A, which are effective, but associated with toxicity and
adverse effects which may limit their long-term use. Although effective as well, data on the long-term safety of newly
introduced biologic agents are still not available. Herein, we present our clinical experience with rifampicin in the
treatment of psoriasis, and review of literature regarding its potential mechanisms of action.
P
soriasis is a T-cell-mediated autoimmune inflammatory disease (1, 2). It significantly affects the
quality of life of patients suffering from psoriasis and
their families (3). The therapeutic goal is to obtain
satisfactory disease control, and improve patients’
quality of life. Conventional systemic therapy
includes methotrexate, cyclosporine, retinoids and
psoralen ultraviolet A, which are used in the treatment
of the disease, but they are associated with toxicity
and adverse effects, which may limit their long-term
use (4). In recent years, new biological agents such
as etanercept, efalizumab, alefacept, infliximab, and
adalimumab have been introduced (5). Although
effects of some of these new agents have been evaluated
for longer periods of continuous use, the majority of
data concerning their usage have been obtained only
for short-term treatment.
We started using rifampicin in the treatment of
psoriasis in 1992 (6-8). Kazandjieva et al., reported
on four patients with tuberculosis treated with
rifampicin (9-10) who suffered from concomitant
psoriasis. The authors observed complete clearance
of the psoriatic skin lesions during the one-year
treatment with rifampicin. Numerous studies have
been conducted since then (11-16). Recently, Tsankov
et al. hypothesized that rifampicin acts as a mild
immunosuppressive agent (17).
© 2009 The Serbian Association of Dermatovenereologists
Materials and methods
We randomized patients suffering from either guttate
or plaque psoriasis. Patients under 18 years of age
were not enrolled in the study, as well as patients with
a history of liver disease. After an one month-washout period rifampicin therapy was initiated. There was
no Psoriasis Area and Severity Index (PASI) cut-off for
admission into study and no history, or clinical signs
of psoriatic arthritis. All patients included in the study
underwent examination of total blood cell count
and liver enzymes before treatment, once during the
treatment, and at the end of rifampicin therapy. All
patients were informed about the transient orange-red
color of body fluids at the beginning of rifampicin
therapy.
Treatment of guttate psoriasis with rifampicin
A group of 82 patients with guttate psoriasis received
an oral dose of 600 mg of rifampicin for at least 60
days. Only emollients were used for topical therapy.
Psoriasis Area and Severity Index (PASI) was calculated
at baseline, and on the 60th day. The primary end-point
was the reduction of PASI at the end of the therapy.
Streptococcal infections are well-known triggers
of guttate psoriasis (18-21), so guttate psoriasis
patients were divided into two groups according to the
following criteria:
5
N. Tsankov et al.
Alternative treatment of psoriasis
was calculated at baseline and on the 60th day. The
primary endpoint was the reduction of PASI at the
end of the therapy.
1. Clinical evidence of dental, ear, nose, throat
or genitourinary infection;
2. Bacterial culture from the pharynx or vaginal
smear;
3. Positive antistreptolysin titer (>200).
Group A (39 patients; 23 female and 16 male) with evidence of concomitant streptococcal infection.
Group B (43 patients; 21 female and 22 male)
- without evidence of concomitant streptococcal
infection.
The control group included 10 randomly selected
patients with guttate psoriasis (4 female and 6 male;
5 patients had a concomitant streptococcal infection,
and another 5 were without evidence of streptococcal
infection). They were given placebo capsules, labeled
as rifampicin, in the same daily dosage for 60 days,
and emollients.
The usual two-sample t-test was used to compare
the difference between the factor levels. The nonparametric Mann-Whitney U-test was also used. The
t-test was used to compare the average percentage
reduction as well.
Extended treatment of psoriasis with rifampicin
Rifampicin therapy was continued in 20 psoriatic
patients who achieved at least PASI 50 after 60 days.
Thirteen of these patients were from the guttate
psoriasis group, and seven were from the group
with chronic plaque psoriasis. None of the patients
had had previous history of any systemic treatment
for their psoriasis, except phototherapy. The daily
dose of rifampicin remained 600 mg per day orally.
Emollients were given for topical therapy only. The
primary endpoint was the reduction of PASI on the
6th month and lack of exacerbation of the disease
during this period.
Moreover, three patients on the extended
treatment with rifampicin presented with clinical
remission after 6th months and continued rifampicin
therapy (11 months now).
Results
Treatment of chronic plaque psoriasis with rifampicin
Rifampicin was used in 25 patients with chronic
plaque psoriasis and it was administered in the same
daily dose as in the group with guttate psoriasis. PASI
Guttate psoriasis
Results of therapeutic effectiveness of rifampicin
in patients with guttate psoriasis are summarized in
Table 1.
Table 1. Rifampicin treatment of patients with guttate psoriasis
Patients with guttate psoriasis
Group A
Group B
Placebo
39
43
10
Age - years
16 - 68
23 – 71
31 - 59
Gender – female/male
23/16
21/22
4/6
Duration of psoriasis
3 weeks - 13 years
1 – 28 years
2 months – 5 years
Mean PASI at baseline
8.11
8.95
4.82
Mean PASI on the 60th day
2.06
2.57
2.93
Mean PASI reduction
75%
71%
39%
PASI 50 – number of patients (%)
28 (72%)
30 (70%)
3 (30%)
20 (51%)
19 (44%)
0
Number of patients
PASI 50, PASI reduction of 50% at the end of the therapy; PASI 75, PASI reduction of 50% at the end of the therapy
6
ORIGINAL STUDY
The t-test for two independent groups was
used to compare differences. The t-test did not show
statistically significant differences between Groups A
and B (p=0.20). This may be due to small samples of
patients and the corresponding great variations in the
groups. The non-parametric Mann-Whitney U-test
also showed no significant differences (p=0.114).
Even when changing PASI at baseline and on 60th
day, in order to make the distributions normal, the
comparison with t-test showed no differences once
again (p=0.14). The t-test was applied to compare the
average percentage reduction as well. However, no
significant difference (p=0.47) was established. In the
group A, the mean PASI decreased from 8.11 (at the
beginning of the therapy) to 2.06 on the 60th day. In
the group B, the mean PASI decreased from 8.95, at
baseline, to 2.57 at the end of the therapy (Figure 1
and Figure 2). Based on the obtained results, it can be
concluded that improvements in group A and group
B are statistically identical (p<0.001).
Comparing the efficacy of rifampicin with
placebo, there is a significant evidence in favor of
rifampicin (p < 0.005).
Three patients reported transient nausea and
vomiting. There were no patients with abnormal
laboratory findings. Blood cell counts and liver
enzymes were normal at baseline, during and at
the end of rifampicin therapy. All patients reported
orange-red urine color, which disappeared after
completion of treatment. None of the patients required
discontinuation of therapy due to side-effects.
Figure 1. The first patient from the group B:
PASI 10.8 score at baseline
Figure 2. The first patient from the group B:
PASI 0.5 score on the 60th day
Chronic plaque psoriasis
The results in chronic plaque psoriasis patients are
summarized in the Table 2.
It was observed that some of the patients achieved
a very good therapeutic response - 12% of them had
PASI 75 scores at the end of treatment. However, some
patients achieved PASI 30. It should be pointed out
that the disease severity index in the chronic plaque
7
N. Tsankov et al.
Table 2. Rifampicin treatment of patients with chronic plaque psoriasis.
Patients with chronic plaque psoriasis
Number of patients
25
Sex – female/male
14/11
Age - years
29 – 69
Duration of psoriasis - years
1 – 25
Mean PASI at baseline
18.05
Mean PASI on the 60th day
9.02
Mean PASI reduction
50.03%
13 (52%)
3 (12%)
PASI 50, PASI reduction of 50% at the end of the therapy; PASI 75, PASI reduction of 50% at the end of the therapy
psoriasis group was greater (mean PASI at baseline
was 18) than the severity index in the guttate psoriasis
group (mean PASI at baseline was 8.48).
Extended treatment of psoriasis with rifampicin
The improvement achieved on the 60th day was
maintained in those patients who continued receiving
rifampicin for 6 months. Ten patients (50%) achieved
PASI 90 after 6 months. All patients with guttate
psoriasis presented with marked improvement (PASI
75) or remission (PASI 90) at the end of the 6-month
period. Three chronic plaque psoriasis patients
maintained remission achieved after 6 months,
through the whole treatment period (Figure 3 and
Figure 4). None of the patients suffered exacerbation
of the disease during the 6 month period of rifampicin
therapy. Three patients on rifampicin therapy have
been followed up for 11 months and they are still
without exacerbation of the disease. None of the
patients demonstrated any clinical or laboratory side
effects during the extended treatment period. The
orange-red urine color disappeared soon after drug
discontinuation.
8
Discussion
We began our clinical studies with rifampicin in
patients with guttate psoriasis, believing that its
antimicrobial properties would be most effective for
this form of the disease. However, data suggesting
immunosuppressive properties of rifampicin have
been available in the literature for more than 30
years. Paunescu et al. suggested that rifampicin
exhibits immunosuppressive properties both in vitro
and in vivo. Specifically, they found that it affects
antibody production and certain cell-mediated forms
of immunity. This action of rifampicin is achieved
if two or four times the therapeutic human doses
are used, and it is reversible in vivo (22). Nilsson et
al. found that stimulated human lymphocytes are
significantly inhibited by rifampicin (23). Gupta et al.
established a considerable T-lymphocyte suppression,
2-3 weeks after the initiation of rifampicin therapy
(24). The cellular suppression, evident after a 28day treatment with rifampicin, is transient when the
drug is discontinued. Mlambo et al. reported that at
high doses rifampicin moderately suppressed TNF-α,
and these findings suggested that rifampicin had
ORIGINAL STUDY
Figure 3. The second patient with chronic plaque
psoriasis: PASI 25.1 score at baseline
Figure 4. The second patient with chronic plaque
psoriasis: PASI 0.8 score on the 6th month
differential immunomodulatory effects on the innate
immune mechanisms (25). Rifampicin may also
inhibit the secretion of IL-1β and TNF-α (26). Calleja
et al. demonstrated that rifampicin both binds to, and
activates, the human glucocorticoid receptor, which
regulates the expression of many genes, including
those encoding interleukins that regulate immune
responses (27). Most recently, Dubrac et al. established
that pharmacologic activation of pregnane X receptor
(PXR) inhibits T-lymphocyte function (28). The
authors showed that PXR agonists, such as rifampicin,
inhibit the expression of CD25, a T-lymphocyte
activation marker, as well as synthesis and production
of the Th1 cytokine IFN-gamma by T-lymphocytes in
a PXR-dependent manner. Moreover, pharmacologic
PXR activation dramatically reduces the ability of
T-lymphocytes to proliferate in response to a strong
immune stimulation.
Tuberculosis is the main indication for rifampicin,
as part of the antituberculotic drug combination where
rifampicin is administered for more than a year. Data
on its side effects and drug interactions have been
reported for more than 35 years of clinical experience
(29-32). We used rifampicin in psoriasis patients for
6 months. Our results in plaque type psoriasis are
preliminary. The number of patients in this group was
too small for statistical significance, and there was no
control group for comparison. We believe that there
are good-responders and nonresponders to rifampicin.
More studies on the use of rifampicin in psoriasis are
necessary. However, our current therapeutic results,
along with the literature data suggest that rifampicin
is a mild immunosuppressive agent which can be used
in all types of psoriasis, but it is most effective in the
guttate psoriasis patients.
Conclusion
Psoriasis is still an incurable disease. Most patients
experience a recurrence after the systemic treatment
with rifampicin (15-45 days) is discontinued. This
9
is evident for all the conventional drugs, even for
new biological agents. Our results are promising in
the continuous search for alternative therapeutic
modalities providing psoriasis patients with periods
of remission and better quality of life. However, due
to its moderate immunosuppressive effect, we believe
that rifampicin can serve as a cheap, effective, and safe
alternative to the new biological agents.
References
1.Krueger JG. The immunologic basis for the treatment of
psoriasis with new biologic agents. J Am Acad Dermatol
2002;46:1-23.
2. Prinz LC. The role of T cells in psoriasis. J Eur Acad Dermatol
Venereol 2003;17:257-70.
3. Eghlileb AM, Davies EE, Finlay AY. Psoriasis has a major
secondary impact on the lives of family members and partners.
Br J Dermatol 2007;156(6):1245-50.
4. Thaci D. Long-term data in the treatment of psoriasis. Br J
Dermatol 2008;159(Suppl 2):18-24.
5. Gottlieb A, Korman NJ, Gordon KB, et al. Guidelines of
care for the management of psoriasis and psoriatic arthritis:
section 2. Psoriatic arthritis: overview and guidelines of care for
the treatment with an emphasis on the biologics. J Am Acad
Dermatol 2008;58(5):851-64.
6. Tsankov N, Krasteva M. Rifampin in severe forms of psoriasis.
J Dermatol Treat 1992;3:69-71.
7. Tsankov NK, Kamarashev JA. Rifampin in dermatology. Int J
Dermatol 1993;32:401-6.
8. Tsankov N, Krasteva M. On rifampin treatment of psoriasis
(letter). J Am Acad Dermatol 1993;29(6): p. 1057.
9. Kazandjieva J, Kamarashev J, Hinkov G. Alleviation of psoriasis
by rifampicin treatment of pulmonary tuberculosis(letter). J
Dermatol Treat 1993;4:163-5
10. Kzandjieva J, Kamarashev J, Hinkov G, Tsankov N.
Rifampicin und Psoriasis. Aktuel Dermatol 1997;23:78-81.
11. Tsankov N. Drug therapy in patients with Psoriasis vulgaris:
risks and perspectives (dissertation). Sofian (Bulgaria): Medical
University; 1996.
12. Grozdev I, Kazandjieva J, Tsankov N. Rifampicin in
eruptive psoriasis (abstract). J Eur Acad Dermatol Venereol
2004;18(Suppl 1):57-8
13. Grozdev I, Kazndjieva J, Tsankov N. Use of rifampicin
for the treatment of psoriasis (abstract). J Eur Acad Dermatol
Venereol 2004;18(Suppl 2):268-9.
14. Tsankov N, Kazandjieva J, Grozdev I. Treatment of psoriasis
with rifampicin. Is rifampicin an immunosuppressive antibiotic?
(poster presentation). European Congress on Psoriasis; 2004 Oct
10
N. Tsankov et al.
21-24; Paris, France. Paris: European Academy of Dermatology
and Venerology; 2004.
15. Tsankov N, Grozdev I. Rifampicin as treatment strategy
for psoriasis: benefits and risks (oral presentation); The 2nd
International Congress on Psoriasis; 2007 June 21-24; Paris,
France. Paris: European Academy of Dermatology and
Venerology; 2007.
16. Tsankov N, Grozdev I, Kazandjieva J. Old drug: new
indication. Rifampicin in psoriasis. J Dermatol Treat
2006;17(1):18-23.
17. Tsankov N, Grozdev I. Rifampicin in treatment of psoriasis.
J Eur Acad Dermatol Venereol 2009;23(1):93-5.
18. Farber EM, Nall L. Guttate psoriasis. Cutis 1993;51:157-64.
19. Yamamoto T, Katayama I, Nishioka K. Clinical analysis
of staphylococcal superantigen hyper-reactive patients with
psoriasis vulgaris. Eur J Dermatol 1998;8:325-9.
20. Valdimarsson H, Baker BS, Jonsdottir I, Powles A, Fry L.
Psoriasis: a T-cell mediated autoimmune disease induced by
streptococcal superantigens. Immunol Today 1995;16:145-9.
21. Leung DY, Gately M, Trumble A, Ferguson-Darnell B,
Schlievert PM, Picker LJ. Bacterial superantigens induce T cell
expression of the skin-selective homing receptor, the cutaneous
lymphocyte-associated antigen, via stimulation of interleukin 12
production. J Exp Med 1995; 181:747-53.
22. Paunescu E. In vivo and in vitro suppression of humoral and
cellular response by rifampicin. Nature 1970;229:1188-9.
23. Nilsson BS. Rifampicin: an immunosuppressant? Lancet
1971;2:374.
24. Gupta S, Grieco MH, Siegel I. Suppression of T-lymphocyte
rosettes by Rifampicin: studies in normals and patients with
tuberculosis. Ann Intern Med 1975;82:484-8.
25. Mlambo G, Sigola LB. Rifampicin and dexamethasone have
similar effects on macrophage phagocytosis of zymosan, but
differ in their effects on nitrite and TNF-alpha production. Int
Immunopharmacol 2003;3:513-22.
26. Ziglam HM, Daniels I, Finch RG. Immunomodulating
activity of rifampicin. J Chemother 2004;16:357-61.
27. Calleja C, Pascussi JM, Mani JC, et al. The antibiotic
rifampicin is a nonsteroidal ligand and activator of the human
glucocorticoid receptor. Nat Med 1998;4:92-6.
28. Dubrac S, Elentner A, Ebner S, Horejs-Hoeck J, Schmuth
M. Modulation of T-lymphocyte function by the Pregnane X
Receptor (PXR). J Immunol 2010;184(6):2949-57.
29. Grosset J, Leventis S. Adverse effects of rifampin. Rev Infect
Dis 1983;5:S440-6.
30. Scheuer PJ, Summerfield JA, Lal S, et al. Rifampin hepatitis.
Lancet 1974;1:421-5.
31. Girling DJ, Hitze HL. Adverse reactions to rifampicin. Bull
WHO 1979;57:45-9.
32. O’Reilly RA. Interaction of chronic daily warfarin and
rifampin. Ann Intern Med 1975;83:506-8.
ORIGINAL STUDY
Alternativna terapija psorijaze: da li rifampicin ima blago
imunosupresivno dejstvo?
Sažetak
Uvod: Psorijaza je učestala inflamatorna bolest
kože koja nastaje usled patološke aktivacije T-ćelija.
Konvencionalna sistemska terapija (metotreksat,
ciklosporin, retinoidi, PUVA tj. psoralen i UVA)
efikasna je, ali usled toksičnosti ovih preparata,
njihova dugotrajna primena je isključena. Iako su
novi biološki agensi takođe efikasni, nedostaju podaci
o njihovoj bezbednosti prilikom duže primene.
Cilj: Zadatak ovog rada je da prikaže kliničko iskustvo
u primeni rifampicina kod bolesnika s psorijazom, kao
i pregled literature koja se bavi njegovim mogućim
mehanizmima delovanja.
Materijal: Ispitivanje je obuhvatilo randomizirani
uzorak, koga su činili oboleli od gutatne ili hronične
plakozne psorijaze sa različitim PASI (eng. Psoriasis,
Area and Severity Index) skorom (predstavlja
standardni metod za kvantitativnu ocenu lokalizacije,
rasprostranjenosti i težine kliničkog nalaza kod
obolelih od psorijaze, usvojen na međunarodnom
nivou). Osobe mlađe od 18 godina i osobe koje su
davale anamnestičke podatke o bolestima jetre, i
artritisu nisu bile uključene u ispitivanje. Svi ispitanici
su dali svoj pismeni pristanak. Pre započinjanja
lečenja, svima je dato objašnjenje o prestanku
narandžasto-crvene prebojenosti urina po prestanku
uzimanja leka. Ukupan broj leukocita i jetreni
enzimi su određivani u tri navrata: na početku, u
toku i na kraju lečenja. Eksperimentalnu grupu su
činile 82 osobe sa gutatom psorijazom i 25 osoba
sa hroničnom plakoznom psorijazom. Svi ispitanici
sa gutatnom psorijazom, podeljeni su u dve grupe:
grupa A, oboleli sa streptokoknom infekcijom (39
osoba) i grupa B, oboleli bez streptokokne infekcije
(43 osobe). Prisustvo ili odsustvo infekcije je
određivano na osnovu sledećih kriterijuma: klinički
manifestna orofaringealna ili genitourinarna infekcija;
biogram brisa uzetog sa sluzokože orofaringealne ili
genitourinarne regije; antistreptollizinski titar >200.
Kontrolnu grupu je činio randomizirani uzorak od 10
osoba sa gutatnom psorijazom, od kojih je 5 bilo sa
streptokoknom infekcijom.
Metode: Svi ispitanici u eksperimentalnoj grupi su
lečeni peroralno kapsulama rifampicina u jednoj
pojedinačnoj dnevnoj dozi od 600 mg, tokom 60
dana. Lečenju je predhodio period bez terapije, u
trajanju od minimum mesec dana. Isti protokol je
primenjen i u kontrolnoj grupi, samo što su ispitanici
umesto rifampicina, dobijali placebo kapsule
etiketirane kao rifampicin. Svim ispitanicima su
lokalno aplikovane indiferentne emolijentne kreme.
PASI skor je određivan nultog dana i šezdesetog
dana lečenja. Za procenu efikasnosti terapije korišćen
je stepen smanjenja PASI skora šezdesetog dana u
odnosu na nulti. Šezdesetog dana lečenja, kod 20
osoba, 13 sa gutatnom i 7 sa plakoznom psorijazom,
utvrđeno je smanjenje PASI skora za najmanje 50%
u odnosu na nulti dan, te je lečenje istim protokolom
nastavljeno. Nakon 6 meseci lečenja, određivan je
PASI skor. Za procenu efikasnosti terapije korišćen je
stepen smanjenja PASI skora u odnosu na nulti dan,
kao i odsustvo recidiva bolesti tokom šestomnesečnog
perioda lečenja.
Rezultati: Nakon 60 dana lečenja, rezultati ispitivanja
efikasnosti terapije sa rifampicinom, dobijeni kod
ispitanika sa gutatnom psorijazom i infekcijom i
gutatnom psorijazom bez infekcije, prikazani su u
Tabeli 1. Rezultati dobijeni u grupi A ispitanika sa
gutatnom psorijazom i streptokoknom infekcijom,
su poređeni sa istim rezultatima dobijenim u grupi B
ispitanika sa gutatnom psorijazom bez streptokokne
infekcije. Nije utvrđena statistički značajna razlika
između ove dve grupe (t-test za dve nezavisne grupe
i neparametrijski Mann-Whitney U-test). Takođe,
šezdesetog dana lečenja nije utvrđena statistički
značajna razlika (pomoću t-testa) između dve grupe
ni u prosečnom smanjenju PASI skora (p=0.47). U
grupi sa infekcijom, prosečan PASI skor je smanjen
šezdesetog dana sa 8.11 koliko je iznosio na početku
lečenja, na 2.06. U grupi sa gutatnom psorijazom
bez infekcije, PASI je snižen sa 8.95 na 2.57 (Slika 1
i 2). Rifampicin je pokazao statistički značajno veći
terapijski efekat u lečenju gutatne psorijaze u odnosu
na terapijski efekat koji je pokazao placebo (p <
0.005). Tokom 60 dana lečenja, samo su 3 ispitanika
imala prolaznu muku i povraćanje, niko od ispitivaih
nije imao poremećaj laboratorijskih parametara, kod
11
svih je nestajala promena u boji urina po prestanku
terapije, niko od ispitanika nije morao da prekine
započeto lečenje. U grupi obolelih sa hroničnom
plakoznom psorijazom (Tabela 2), početna prosečna
vrednost PASI skora je bila viša (PASI =18) u odnosu
na grupu obolelih od gutatne psorijaze (PASI
=8.48). Pojedini ispitanici su postigli dobar terapijski
efekat,12% je imalo smanjenje PASI skora za 75%,
dok su pojedini ispitanici ostvarili smanjenje PASI
skora za samo 30%. U grupi od 20 pacijenata koj kojih
je lečenje rfampicinom nastavljeno, 50% je postiglo
smanjanje PASI skora za 90% nakon 6 meseci lečenja
Kod svih ispitanika sa gutatnom psorijazom, nakon
6 meseci lečenja PASI je smanjen za 75% ili 90% u
odnosu na nulti dan. Svo vreme dok je trajalo lečenje
rifampicinom, ni jedna osoba nije imala recidiv
psorijaze kao ni poremećaj laboratorijskih parametara,
kod svih je nestajala promena u boji urina po prestanku
12
N. Tsankov et al.
terapije. Tri ispitanika su postigla kompletnu remisiju
i kod njih je lečenje nastavljeno. Do recidiva bolesti
nije došlo ni nakon 11 meseci lečenja.
Zaključak: Psorijaza još uvek ostaje u grupi onih
oboljenja kod kojih ne postoji radikalna specifična
terapija, jednako efikasna kod svih obolelih. Kod većine
obolelih koji su lečeni sa rifampicinom, recidiv bolesti
je nastupio 15-45 dana nakon prestanka lečenja, što se
dešava i nakon prestanka lečenja sa konvencionalnim
ali i novim biološlim metodama sistemskog
lečenja. Rezultati ovog ispitivanja pokazuju da bi se
imunosupresivno dejstvo rifampicina moglo upotrebiti
u lečenju obolelih od gutatne psorijaze, kao efikasna i
bezbedna jeftina terapijska alternativa novim biološkim
agensima. Potrebna su dalja ispitivanja sprovedena na
značajno većem broju obolelih, kako bi se precizno
evaluirala efikasnost rifampicina i bezbednost njegove
primene u terapiji različitih formi psorijaze.
REVIEW ARTICLE
Treatment of acne vulgaris: a literature review
Milica SUBOTIĆ*,Verica ĐURAN
Clinic of Dermatovenereology Diseases, Clinical Center of Vojvodina, Novi Sad, Serbia
*Correspondence: Milica Subotic, E-mail: [email protected]
UDC 616.53-002-08
Abstract
Acne vulgaris is a common skin disease, which affects individuals of all races and ages. In Caucasians, almost
85% of individuals between 12 and 25 years, as well as 25% of adults, are affected with some forms of acne. The
pathophysiology of acne is multifactorial, and thus, the treatment must cover all the possible causes of acne. For this
reason, acne therapy is mostly a combination therapy, with the main goal to achieve clinical improvement, without
scarring and residuals, as much as possible. The treatment should be planned individually, depending on the clinical
appearance, severity and psychological profile of the patient. The treatment usually takes time and requires dedication
and patience of both the patient and the physician.
A
cne vulgaris is a chronic inflammatory disease
of pilosebaceous unit, which is characterized by
noninflammatory (opened or closed comedones) and
inflammatory (papules, pustules, nodules) skin lesions.
The lesions generally affect the face, chest and back,
skin regions with greatest density of sebaceous glands.
The prevalence of facial acne in adolescent population
ranges from 81% to 95% in boys, and 79% to 82%
in girls (1). The peak incidence is between 14 and 17
years in girls, and 16 and 19 years in boys.
At least four factors are important in the
development of acne: plugging of the hair follicle with
abnormally cohesive desquamated cells, genetically
predisposed sebaceous gland hyperactivity, colonization
of the sebaceous follicles with bacteria (especially
Propionibacterium acnes - P. acnes), inflammation and
immune response (2). The first pathological change is
comedo formation. If a closed comedo or microcomedo
erupts, an inflammatory reaction ensues, resulting in the
formation of papules, pustules, nodules and pseudocysts.
Furthermore, P. acnes contribute to the inflammatory
response and release of proinflammatory mediators.
Although acne is not an inherited condition, obviously
there is a genetic predisposition to acne. Several genes
are believed to be involved, of which only cytochrome
P-450-1A1 gene, and the steroid 21-hydroxylase gene
are documented (3). Positive family history of acne is
obtained in 40% of patients and correlates with more
severe forms (4). Scarring may also occur, but it is not
in direct correlation with the severity of inflamed acne.
There are different types of scars and it can be associated
with loss of collagen fibers which causes ice pick scars
and atrophic macular scars, while with collagen increase,
hypertrophic scars develop.
Acne and acne scarring, especially on the face, may
be the reason of psychological and social disability in
some patients. Anxiety, depression, social withdrawal,
decreased self-esteem, embarrassment, frustration are
reported in many patients (5, 6, 7). For this reason,
assessment of the degree of psychosocial disturbances is
important in planning acne treatment.
The treatment choice for acne depends on several
important factors: severity of acne; type of acne lesions;
presence of scarring; psychological and social impact of
the disease on the individual. Acne assessment using the
Leeds Acne Grading Scale is very useful, practical, easy
to use (8). Generally, acne can be classified into three
categories: mild (mainly non-inflammatory lesions);
moderate (non-inflammatory and inflammatory lesions,
such as papule, pustule, small nodules) and severe
(nodules and pseudocysts). Presence of scarring and
significant psychological and social disability can be the
reason to use aggressive therapy depending on the acne
grade (9).
13
M. Subotić and V. Đuran
Treatment of acne vulgaris
Topical treatment
Isotretinoin
Topical treatment is the first choice in acne treatment:
as monotherapy in mild forms of acne, or in
combination with systemic agents in moderate and
severe cases. Topical medications are active only where
and when they are applied, whereas their main action
is prevention of new lesions.
Isotretinoin (13-cis retinoic acid) is available as 0.05%
gel, and 0.05% and 0.01% cream. Topically applied,
it has similar effectiveness as tretinoin, but with less
skin irritation. In contrast with the oral formulation,
it neither reduces the size of sebaceous glands nor
suppresses sebum production.
Topical retinoids
Topical retinoids represent a mainstay of acne treatment
because of theirs effects: they reduce microcomedone
formation and number (precursors of lesions),
resolve mature comedones, reduce inflammatory
lesions, promote normal desquamation of follicular
epithelium, they have anti-inflammatory activity,
enhancing increased penetration of other drugs (such
as topical antibiotics, resulting in synergistic effects),
and maintain remission of acne by inhibiting comedo
formation, and thus preventing new lesions.
Retinoids used for acne treatment include:
tretinoin and isotretinoin (first generation retinoids);
monoaromatic retinoids, such as motretinide, a second
generation monoaromatic retinoid; and adapalene
and tazarotene, a third generation retinoids. Retinol
and retinaldehyde are also used (10).
Adapalene
Tretinoin
Tretinoin (all-trans retinoic acid), the first topical
retinoid developed for acne treatment is available in
cream: 0.025%, 0.01%, 0.05%, 0.1%; in gel 0.1%,
0.025%; in liquid form: 0.05%; 0.1% and 0.2%; a
0.05% ointment; in 0.05% compresses, in 0.1%
gel microsphere and in form of a 0,025% polymer
cream. This agent is known to bind to and activate
all three retinoic acid receptors, (RAR) subtypes, and
the cellular retinoic acid binding protein (CRABP). It
acts by increasing the turnover of follicular epithelial
cells and by accelerating the shedding of corneocytes,
and thus, normalizes keratinization. In this way, it
causes significant reduction of noninflammatory
and inflammatory acne lesions. Skin irritation, its
commonest side-effect, can be diminished with
new, liposomal encapsulated tretinoin formulation
(gel or cream formulation, which contains
polyoprepolymer-2), a large polymer compound that
delays absorption of tretinoin in epidermis (11, 12).
14
Adapalene is a third-generation naphthoic acid
derivative of retinoic acid, that selectively binds to
RAR-beta and-gamma subtypes, and activates gene
expression through all three RARs. It is available
as a 0.1% and 0.3% gel, and as a 0.1% cream
(13, 14). Adapalene shares some of the biological
characteristics of tretinoin, but has different
physicochemical properties, including increased
chemical and light stability (for this reason it can
be used during the day) and high lipophilicity. It
modulates cellular keratinization and inflammatory
processes, and inhibits lipoxygenase activity and
oxidative metabolism of arachidonic acid. This drug
is the FDA pregnancy category C, and should be used
with caution in pregnant women. Some studies have
shown that a major congenital malformation rate of
1.9% occurred in mothers who used topical retinoid
during the first trimester of pregnancy, versus 2.6% in
mothers who were not exposed to retinoid (15).
Tazarotene
Tazarotene (also belongs to the third-generation of
retinoids) is an acetylenic retinoid, which penetrates
the skin and it is converted to an active metabolite,
tazarotenic acid, which has a high affinity for RAR-beta
and RAR-gamma. The mechanisms of its action are
extensively studied on psoriatic skin lesions, and they
enhanced normalization of keratinocyte proliferation
and differentiation, as well as reduction in keratinocyteexpressed markers that attract inflammatory cells
(16). Similar to other topical retinoid, the main sideeffects are skin peeling, dryness and redness, burning,
and itching. The recommended short term therapy
(between 30 seconds and 5 minutes) showed good
tolerability and acne improvement (17). Tazarotene
is in the FDA pregnancy category X, so it should
not be used during pregnancy and breastfeeding. It
proved to be teratogenic in animals, after systemic
REVIEW ARTICLE
administration of high doses, but not after topical
exposure.
Motretinide
Mortified is a second-generation monoaromatic
retinoid which is slightly less effective than retinoid,
but it is also less irritant. This agent is available as a
0.1% cream and solution in Switzerland (18).
Retinaldehyde
Retinaldehyde, a key intermediate molecule in the
metabolism of natural retinol by keratinocytes, has
mild comedolytic effects and antibacterial activity
against Gram-positive bacteria, including P. acnes.
On the market, it is available as Diacneal® (0.1%
retinaldehyde, 6% glycolic acid) for cosmetic therapy,
and for clinical trials as a 0.5-1% cream.
After achieving positive results in acne
treatment, retinoids are very important and suitable
for maintenance therapy. It is well known that
comedo formation occurs 2-6 weeks after cessation of
treatment. For this reason, long-term application (of
several years duration) of retinoids is recommended to
prevent microcomedone formation.
Topical antibiotics
Topical antibiotics are used in the treatment of mild
inflammatory acne. The most widely used agents are:
clindamycin (available as a 1% gel, solution and lotion)
and erythromycin (available as a 1% and 2% solution;
as a 2% ointment and 2% and 4% gel) (18, 19, 20).
The primary action of these agents is to reduce the
P. acnes population on the skin surface, especially
within follicles. They also exhibit a mild comedolytic
effect, reducing P. acnes and interleukin-1 production.
They demonstrate a mild anti-inflammatory effect
by suppressing leukocyte chemotaxis. However,
these agents should not be used as monotherapy; if
monotherapy is necessary, it should be used for a short
(3-4 weeks) period. This is due to a dramatic increase
in bacterial resistance during the past 20 years (21,22),
and unsatisfactory results, especially of erythromycin,
and clindamycin. The reason why the efficacy of topical
clindamycin has remained stable, despite an increased
resistance of P. acnes, may be due to nonbacterial
effects of this local antibiotic, such as inhibition of
leukocyte chemotaxis or inhibition of extracellular
lipase production by Propionibacteria (23). The topical
antibiotic therapy should be discontinued after the
resolution of inflammatory lesions or, if there is no
improvement after 6-8 weeks of treatment, alternative
therapy should be considered.
Benzoyl peroxide
Benzoyl peroxide is one of the most commonly used
topical agents in acne treatment. It has strong antiinflammatory, anti-microbial, and anti-comedogenic
effects, so it is frequently used as first-line therapy for
mild to moderate acne. It is available as gel, cream,
lotion and solution at different concentrations (2.5%,
3%, 4%, 5%, 10%) (24). The main side-effects,
erythema, scaling and itching, can be controlled by
less frequent application. Long-term administration
of this agent causes no skin damage and there is no
evidence of acquired bacterial resistance.
Azelaic acid
Azelaic acid, naturally occurring saturated dicarboxylic
acid, inhibits DNA synthesis of keratinocytes, has
some comedolytic activity and antimicrobial effects
on Staphylococcus epidermidis and P. acnes. On the
market, it is available as 20% cream and 15% gel (25).
However, it shows less effective results when compared
to antibiotics; it can also be used in the treatment of
postinflammatory hyperpigmentation.
Dapsone gel 5%
Dapsone is a sulfone with anti-inflammatory and
antimicrobial properties (26). It has been available for
over 60 years and proved effective in the treatment of acne,
including inflammatory, nodulocystic acne. However,
systemic administration of dapsone in acne treatment
has never been widely accepted because of its toxicity
and influence on dose-induced hemolytic anemia, due
to production of hydroxylamine metabolite. Individuals
with glucose-6-phosphate dehyrdogenase (G6PD)
deficiency are more susceptible to developing hemolytic
anemia (especially male patients, because G6PD enzyme
is located on the X chromosome). Administration of
dapsone as a 5% aqueous gel is a clinically-effective dose,
with minimal systemic absorption, and approved safety
(25, 26). Local irritation is minimal. New anti acne
agents may be used to prevent the increasing prevalence
of antibiotic-resistant strains of P. acnes.
15
Topical hormone therapy
Knowing that increased sebum production is due
to androgens acting at the genetically predisposed
sebaceous follicle, attempts to include hormones
in acne treatment have been promoted. Hormone
therapy may include of antiandrogens (cyproterone
acetate, spironolactone) and enzyme inhibitors that
are involved in androgen metabolism in the skin.
Topical administration of cyproterone acetate
showed the same effectiveness as oral antiandrogen
medications, with reduced risk of adverse effects,
avoiding high serum cyproterone acetate levels (29).
Other topical treatment modalities
Phototherapy
Phototherapy includes visible light and photodynamic
therapy. P. acnes are Gram-positive anaerobic bacteria
that produce and accumulate porphyrins. Irradiation
of bacterial colonies with blue visible light (peak
irradiation at 415 nm) and mixed blue and red
light (peaks of irradiation at 415 and 660 nm) leads
to photoexcitation of bacterial porphyrins, singlet
oxygen formation, and bacterial destruction (30,31).
Addition of delta-aminolevulinic acid (ALA) enhances
intracellular porphyrin synthesis. Significant adverse
effects, such as discomfort during the treatment,
transient hyperpigmentation, superficial exfoliation,
erythema, crust formation, duration of treatment (45
minutes per session for truncal acne) are reasons why
this therapeutic modality is not yet widely accepted
(32).
Administration of coherent LASER light
(infrared 1450 nm diode laser) may be useful in acne
treatment, as a safe and effective method. However,
this laser causes thermal coagulation of the sebaceous
lobule and associated hair follicule, reducing both
sebaceous gland secretion and inflammation (33).
Chemical peel
Three types of chemical peels are used: superficial
(Jessner peels, glycolic acid and lactic acid peels
35 - 50%, trichloroacetic acid (TCA) 10 - 30%);
intermediate (TCA 30 - 50%); deep (phenol)
peels. Superficial peels show the best benefit-risk
ratio in all anti-acne scar treatments, by reducing
postinflammatory hyperpigmentation, macular
erythematous scars and size of dilated pores. The
16
extent of peeling depends on the anatomic site
of application, presence or absence of seborrhea,
integrity of epidermis, agent concentration, number
and duration of applications. Erythema, desqumation,
crusting, folliculitis, hyper or hypopigmentation and
flare of acne lesions may be consequences of peeling
(34).
Skin surgery
Mechanical removal of lesions (open and closed
comedones) with comedo extractor can also be helpful.
Punch excision and elevation, skin grafting and
subcision are surgical methods which can be applied
depending on the type of acne residues. Injections
of steroids and liquid nitrogen can be initial steps in
treatment of hypertrhopic and keloid scars (35).
Systemic treatment
Oral antibiotics
Systemic antibiotic therapy is primarily used in
moderate-to-severe inflammatory acne, acne resistant
to topical treatment, and in acne affecting large body
surface. Tetracyclines and their derivatives (doxycycline,
minocycline), are the most widely used antibiotics, as
well as macrolides (erythromycin) and trimethoprim/
sulfamethoxazole. When choosing antibacterial agents,
one should take into account the efficacy, costeffectiveness, benefit-risk ratio, patients’ acceptability
and potential development of resistance (36).
Tetracycline is a safe and efficient agent for acne
vulgaris. The initial dose is 500 mg twice a day for
an average time of 6 weeks, and after the decrease
of inflammation, the dose should be reduced to 500
mg per day. The main side-effects are gastrointestinal
symptoms, such as diarrhea, vomiting, dyspepsia, and
vaginal candidiasis in women. Tetracycline causes
enamel hypoplasia and yellowish teeth in children.
Doxycycline, a second generation tetracycline,
shows excellent penetration in to the pilosebaceous
unit. The initial dose is 100 mg twice a day. It
exhibits the same side-effects as tetracycline, but
photosensitivity is the most prominent (also photoonycholysis).
Minocycline is considered to be the most
effective tetracycline, with the lowest rate of resistance
to P. acnes (also in cases of cross-resistance to other
tetracyclines) (37). The initial dose is 50-100 mg twice
REVIEW ARTICLE
a day, while the maintenance dose is 50-100 mg a day.
The main side-effects are skin discoloration (especially
parts of the skin with inflammatory lesions and scars)
and more pronounced CNS adverse effects, such as
vertigo, dizziness and ataxia. Minocycline is also
associated with serious adverse effects, which were first
reported in 1992, (case of minocyclin-induced lupus)
(38). Other drug-induced syndromes associated with
this agent are autoimmune hepatitis, serum sickness
and vasculitis.
Erythromycin is a macrolide antibiotic, which is
effective in inflammatory lesions, but it is frequently
associated with resistant strains. The initial dose is 500
mg twice a day. It causes gastrointestinal side-effects
(vomiting, diarrhea, flatulence), but it can be used
during pregnancy.
Trimethoprim/sulfamethoxazole is effective and
inexpensive, but it is used as a third-line antibacterial
agent in acne treatment, due to potential serious
adverse effects, such as: Stevens-Johnson syndrome,
toxic epidermal necrolysis and bone-marrow
suppression.
Azithromycin (500 mg three times a week during
8 weeks) has recently been added to the list of systemic
antibiotics; it shows good bacteriostatic activity, no
reported bacterial resistance, good tolerance, and few
gastrointestinal disturbances, such as heartburning
and nausea; it can be used during the summer, because
no photosensitivity reactions have been reported (39).
The arising problem in acne treatment is
development of resistant strains of P. acnes, which
has increased from 20% in 1988, to around 25% in
1990, 43% in 1993, and 62% in 1996 (23). In order
to prevent this increasing problem, antibacterials
should be prescribed for 6 months on average; if
retreatment is required, the same antibiotic should be
used; concomitant use of oral and topical, chemicallydifferent antibiotics, should be avoided.
Isotretinoin
Isotretinoin is an oral retinoid used to treat severe
nodulo-cystic acne, moderate or severe acne not
responding to conventional oral and topical therapies,
acne with marked scarring and acne patients with
psychological problems, such as severe depression or
dysmorphophobia (40, 41). It is also used in gramnegative folliculitis, pyoderma faciale and severe acne
rosacea. Isotretinoin targets all pathogenic elements of
acne: by decreasing the size and secretion of sebaceous
glands, it normalizes follicular keratinization and
prevents formation of new comedones; it indirectly
inhibits P. acnes growth, by changing the follicular
milieu, and shows anti-inflammatory effects (42). The
oral dose ranges from 0.1 to 2 mg/kg (the average
initial dose is 0.5 mg/kg; maximal 1 mg/kg; total
cumulative dose of 120-150 mg/kg).
Isotretinoin is commonly used as monotherapy,
except in cases of acne fulminans or pyoderma
faciale, when it is used with oral corticosteroids and
nontetracycline antibiotics. Common side-effects are
dry and fragile skin, dry or cracked lips, nosebleeds,
and rarely headache. Last reports from December
2009, (43), indicated that isotretinon can cause severe
side-effects, such as erythema multiform, Steven-Jones
syndrome and toxic epidermal necrolysis. Routinely,
serum lipids and standard liver function tests should
be regularly monitored. However, it should be used
with great caution in women of child-bearing age, due
to its potential teratogenic effects, and they should
start therapy only after negative pregnancy test results.
Adequate contraception is essential before, during and
2 month after therapy. Depression, which is usually
reported in association with isotretinoin therapy, is
considered as an idiosyncratic side-effect in 1% of
cases (44).
On the other hand, treatment of severe acne
with isotretinoin has shown to reduce anxiety and
depression in patients (45).
After one course of isotretinoin therapy, 38%
of patients had no acne; acne was controlled with
topical therapy in 17%, and with topical therapy and
oral antibiotics in 25% of patients. A second course
of isotretinoin was necessary in 20% of patients (46).
Hormonal therapy
Hormonal therapy for acne is an option for women
who need oral contraception for gynecologic reasons
(contraception, menstrual disturbances), and for
female patients with severe seborrhea, acne, hirsutism
and female androgenic alopecia. Reduction of sebum
secretion is the main effect of hormonal therapy, which
is, one of the multiple events in acne pathogenesis.
Because of that, this therapy is not a first-line choice,
and it is often combined with other anti-acne agents.
Hormonal therapy includes several different
17
antiandrogens: androgen receptor blockers (cyproterone
acetate, spironolactone, flutamide), ovarian or
adrenal androgen production inhibitors (estrogens,
oral contraceptives, cyproterone acetate, low-dose
corticosteroids) and 5-alpha reductase inhibitors (2).
Cyproterone acetate is a progestational antiandrogen, which is combined with ethinyl estradiol
in oral contraceptive formulations, which is widely
used in Europe. This agent causes several side-effects,
such as leg edema, breast tenderness, fluid and sodium
retention, headache, fatigue, liver dysfunction and
blood clotting disorders (47).
Spironolactone is an androgen receptor blocker
and an inhibitor of 5-alpha reductase; 50 or 100
mg twice a day may improve inflammatory acne. It
may cause hyperkalemia, irregular menstrual periods,
fatigue, breast tenderness and headache (48).
Estrogens combined with progestin (to avoid the
risk of endometrial cancers associated with unopposed
estrogens) are commonly used as antiacne agents.
Ovarian production of androgens is suppressed by
direct gonadotropin suppression and prevention of
ovulation. An important side-effect of this therapy
is venous thromboembolism, and can be resolved
with reduced doses of estrogens. Other side-effects
are transient, including nausea/vomiting, breast
tenderness, leg edema and weight gain.
Glucocorticoids can suppress adrenal androgen
production when administrated in low doses. They
can be helpful in the treatment of patients (of both
sexes) with elevated serum level of testosterone and
dehydroepiandrosterone. Moreover, they can be
used orally in combination with isotretinoin in the
treatment of acne fulminans and pyoderma faciale.
Inhibitors of 5-alpha reductase (Flutamide) are
currently not available for acne treatment. They are
registrated in the treatment of prostate cancer, and
there are some attempts to treat acne and androgenic
alopecia in menopausal women (49).
Zileuton
Zileuton, a 5-lipoxygenase inhibitor, reduces the
number of inflammatory lesions in moderate
acne and inhibits the synthesis of sebaceous lipids
(50). Metabolism of arachidonic acid (AA) via the
5-lipoxygenase pathway enchases leukotriene-B4
(LTB4) synthesis, interleukin-6 (IL-6) release and
18
increases intracellular neutral lipids in human sebocytes
(51). Zouboulis et al. (52) investigated the role of
zileuton (a drug which is widely used in the treatment
of chronic asthma) on moderate inflammatory acne
(4x 600 mg/day, orally, for 3 months) and found
that zileuton directly inhibits sebum synthesis in a
transient manner with a potency similar to low-dose
isotretinoin.
Future of acne treatment
The analysis of the genome sequence and of P.
acnes bacteriophage (53), is the basis for genetic
manipulation with the host bacterium. Such therapy
would overcome the problems with resistance of P.
acnes, which results from long-term use of antibiotics.
An inactivated P. acnes vaccine, targeted the whole
bacterium, has been successfully tested in mice.
It showed improvement in inflammatory acne.
Because the induction of cytokines, chemokines and
metalloproteinases by P. acnes occurs via Toll-like
receptor 2 (TLR2)-dependent pathway, development
of vaccines or other immune therapies targeting TLR2,
and other TLRs, may provide other alternatives to
conventional therapy (54). Agents that modulate the
TLR response and downregulate TLR2 expression
and function, indicate that vaccine with potent antiTLR immunity might be the promising antiacne
therapy (55).
References
1. Lello J, Pearl A, Arroll B. Prevalence of acne vulgaris in Auckland
senior high school students. N Z Med J 1995;08:287-9.
2. Gollnick H,Cunliffe W, Berson D, et al. Management of
acne: a report from Global Alliance to Improve Outcomes in
Acne. J Am Acad Dermatol 2003;49(1 Suppl):S1-37.
3. Kubba R, Ajaj AK, Thappa DM, et al. Acne in India: guidelines
for management-IAA consensus document. Genetics in acne.
Indian J Dermatol Venereol Leprol 2009;75(Suppl 1):S4.
4. Cunliffe WJ, Gollnick HPM. Acne: diagnosis and
management. London: Martin Dunitz; 2001.p.1-46.
5. Yazici K, Baz K, Yazici AE, Kokturk A, Tot S, Demirseren D,
et al. Disease-specific quality of life associated with anxiety and
depression in patients with acne. J Eur Acad Dermatol Venerol
2004;18:435-9.
6. Dreno B. Assessing quality of life in patients with acne
vulgaris. Am J Clin Dermatol 2006;7(2):99-106.
7. Ahmed S, Ahmed I. Frequency and magnitude of anxiety and
depression among acne patients: a study of 100 cases. J Liaquat
Uni Med Health Sci 2007;6(1):25-9.
8. Burke BM, Cunliffe WJ. The assessment of acne vulgaris:
leeds technique. Br J Dermatol 1984;111:83-92.
REVIEW ARTICLE
9. Baldwin H. Tricks for improving compliance with acne
therapy. Dermatol Ther 2006;19:224-36.
10. Thielitz A, Gollnick H. Topical retinoids in acne vulgaris.
Am J Clin Dermatol 2008;9(6):369-81.
11. Webster GF. Topical tretinoin in acne therapy. J Am Acad
Dermatol 1998;39: S38-44.
12. Lucky AW, Cullen SI, Jarratt MT, et al. Comparative
efficacy and safety of two 0.0025% tretinoin gels: results from
multicenter double-blind, parallel study. J Am Acad Dermatol
1998;38(4):S17-23.
13. Irby CE, Yentzer BA, Feldman SR. A review of adapalene in
the treatment of acne vulgaris. J Adolesc Health 2008;43:421-4.
14. Laboratories, Differin (adapalene) 0.3% gel product insert
information, United States (online). Available from: URL:http://
www.differin.com/AboutDifferin/ProductInsert_Gel 0,3. aspx
[Accessed 2010 Jan 28].
15. Jick SS, Terris BZ, Jick H. First trimester topical tretinoin
and congenital disorders. Lancet 1993;341:1181-2.
16. Chandraratna RA. Tazarotene: the first receptor-selective
topical retinoid for the treatment of psoriasis. J Am Acad
Dermatol 1997;37(Suppl 2 Pt 1):S12-7.
17. Bershad S, Kranjac, Singer G, Parente J, Tan MH, Sherer D,
Persuad AN, et al. Successful treatment of acne vulgaris using a
new method. Arch Dermatol 2002;38:481-9.
18. Krautheim A, Gollnick H. Acne: topical treatment. Clin
Dermatol 2004;22:398-407.
19. Simonart T, Dramaix M. Treatment of acne with topical
antibiotics: lessons from clinical studies. Br J Dermatol
2005;153:395-403.
20. Poljački M, Subotić M, Đuran V, Matic M, Ivkov M.
Terapija vulgarnih akni lokalnom elektroforetskom primenom
klindamicina. U: II Kongres pedijatara Jugoslavije: zbornik
sažetaka; 1998 sept. 20-26; Novi Sad, Jugoslavija. Novi Sad:
Udruženje pedijatara Jugoslavije; 1998. str. 303-5.
21. Coates P, Vyakrnam S, Eady EA, Jones CE, Cove JH,
Cunliffe WJ. Prevalence of antibiotic-resistant propionibacteria
on the skin of acne patients:10-year surveillance data and
snapshot distribution study. Br J Dermatol 2002;146:840-8.
22. Ross JI, Snelling AM, Carnegie E, Coates P, Cunliffe WJ,
Bettoli V, et al. Antibiotic-resistant acne: lessons from Europe.
Br J Dermatol 2003;148:467-78.
23. Cooper AJ. Systemic review of Propionibacterium acnes
resistance to systemic antibiotics. Med J Aust 1998;169:259-61.
24. Lookingbill DP, Chalker DK, Lindholm JS. Treatment
of acne with combination of clindamycin/bezoylperoxyd gel
compared with clindamycin gel, benzoylpreoxyde gel and
combined results of two double blind investigations. J Am Acad
Dermatol 1997;37:590-5.
25. Katsambas A, Graupe K, Stratigos J. Clinical studies of 20%
azelaic acid cream in the treatment of acne vulgaris. Comparison
with vehicle and topical tretinoin. Acta Derm Venereol Suppl
(Stockh) 1989;143:35-9.
26. Zhu YI, Stiller MJ. Dapsone and sulphones in dermatology:
overview and update. J Am Acad Dermatol 2001;45:420-34.
27. Draelos ZD, Carter E, Maloney MJ, Elewski B, Poulin Y,
Lynde C, et al. Two randomized studies demonstrate the efficacy
and safety of dapsone gel, 5% for the treatment of acne vulgaris.
J Am Acad Dermatol 2007;439:e1-10.
28. Piette W, Taylor S, Pariser D, Jarratt M, Pranav S, Wilson D.
hematologic safety of dapsone gel 5%, for topical treatment of
acne vulgaris. Arch Dermatol 2008;144:1564-70.
29. Gruber D, Sator M, Joura E, Kokoschka EM, Heinze G,
Huber J. Topical cyproterone acetate treatment in women with
acne. Arch Dermatol 1998;134:459-63.
30. Papageorgiou P, Kartsambas A, Chu A. Phototherapy with
blue (415 nm) and red (660 nm) light in the treatment of acne
vulgaris. Br J Dermatol 2000;142:973-8.
31. Charakida A, Seaton E, Charakida M, Mouser P, Avgerinos
A, Chu A. Phototherapy in the treatment of acne vulgaris. Am J
Clin Dermatol 2004;5(4):211-6.
32. Morton CA, et al. Guidelines for topical photodynamic
therapy: report of a workshop of the British Photodermatology
Group. Br J Dermatol 2002;146:552-67.
33. Friedman P, Ming J, Kimyai-Asadi A, Goldberg L. Treatment
of inflammatory facial acne vulgaris with the 1450-nm diode
laser: a pilot study. Dermatol Surg 2004;30:147-51.
34. Goodman GJ. Management of post-acne scarring. What are
the options for treatment? Am J Clin Dermatol 2000;1:3-17.
35. Dreno B. Acne: physical treatment. Clin Dermatol
2004;22:429-33.
36. Tan HH. Antibacterial therapy for acne. Am J Clin Dermatol
2003;4(5):307-14.
37. Garner SE, Eady EA, Popescu C, et al. Minocycline for
acne vulgaris: efficacy and safety. Cochrane Database Syst Rev
2000;(2):CD002086.
38. Sturkenboom MC, Meier CR, Jick H, et al. Minocyclin
and lupus-like syndrome in acne patients. Arch Intern Med
1999;28:392-7.
39. Bardazzi F, et al. Azitromycin: a new therapeutical strategy
for acne in adolescents. Dermatol Online J 2008;13(4):4.
40. Cooper AJ. Treatment of acne with isotretinoin:
recommendations based on Australian experience. Aust J
Dermatol 2003;44:97-105.
41. Poljački M, Gajinov Z, Subotić M, Đuran V, Matić M.
Izotretinoin u dermatoloskoj praksi. Med Pregl 1996;49(56):199-202.
42. Blomhoff R, Blomhoff HK. Overview of retinoid metabolism
and function. Int J Neurobiol 2006;66:606-30.
43. Reactive Holding Statement for postmarketing reports of
severe skin reactions with use of isotretinoin. Basel: Roche; 2009.
44. Chee Hong Ng, Schweitzer I. The association between
depression and isotretinoin use in acne. Ausst N Z J Psychiatry
2003;37(1):78-84.
45. Rubinow DR, Peck GL, Squillace KM, et al. Reduced anxiety
and depression in cystic acne patients after successful treatment
with oral isotretinoin. J Am Acad Dermatol 1987;17:25-32.
46. White GM, Chen W, Yao J, et al. Recurrence rate after first
course of isotretinoin. Arch Dermatol 1998;134:376-8.
47. Huber J, Walch K. Treating acne with oral contraceptives:
use of lower doses. Contraception 2006;73:23-9.
48. Muhlemann MF, Carter GD, Cream JJ, Wise P. Oral
spironolactone: an effective treatment for acne vulgaris in
women. Br J Dermatol 1988;115:227-32.
49. Thilboutot D. Acne: hormonal concepts and therapy. Clin
Dermatol 2004;22:419-28.
50. Zouboulis C, Nestoris S, Adler YD, et al. A new concept for
acne therapy: a pilot study with zileuton, an oral 5-lipooxygenase
inhibitor. Arch Dermatol 2003;139:668-70.
19
51. Zouboulis CC, Seltmann H, Alestas T. Zileuton prevents
the activation of the leukotriene pathway and reduces sebaceous
lipogenesis. Exp Dermatol 2010;19:148-50.
52. Zouboulis CCh, Saborowski A, Boschnakow A. Zileuton,
an Oral 5-lipoxygenase inhibitor, directly reduces sebum
production. Dermatology 2005;210:36-8.
53. Farrar M, Howson K, Bojar R, et al. Genome sequence and
analysis of a Propionibacterium acnes bacteriophage. J Bacteriol
2007;189(11):4161-7.
54. Nakatsuji T, Liu YT, Huang CP, Gallo R, Huang CM.
antibodies elicited by inactivated Propionibacterium acnesbased vaccines exert protective immunity and attenuate the IL-8
production in human sebocytes: prevalence to therapy for acne
vulgaris. J Invest Dermatol 2008;128:2451-7.
55. Kim J. Acne vaccines: therapeutic option for the treatment
of acne vulgaris? J Invest Dermatol 2008;128:2451-7.
Lečenje običnih akni (acne vulgaris) – pregled literature
Sažetak
Definicija: Obične akne (lat. acne vulgaris) predstavljaju hronično inflamatorno oboljenje pilosebacealne
jedinice, koje se učestalo javlja u doba puberteta.
Epidemiologija: Smatra se da oko 85-100% adolescenata i mlađih odraslih u uzrastu 12-24 godine,
boluje od ovog oboljenja godinama (bar povremeno).
U grupi adolescenata, učestalost i težina kliničke slike,
kao i sklonost ožiljavanju je veća kod muškaraca, dok
je sklonost ka perzistiranju promena i nakon puberteta
više izražena kod osoba ženskog pola.
Patofiziologija: U nastajanju akni učestvuje više faktora.
Rane karakteristike oboljenja, kao što su seboreja
i formiranje komedona, posledica su androgene
sekrecije adrenalnog porekla. Sa postepenim razvojem
gonadalne aktivnosti, androgeni poreklom iz testita i
ovarijuma, dovode, na nivou genetski predisponiranih
folikula, do više izražene seboreje i komedogeneze.
Drugi faktori koji su odgovorni za formiranje
komedona su iritantni efekat lipidnih sastojaka
sebuma, aktivnost lokalnih citokina, naročito
interleukin 1- alfa i kolonizacija mikroorganizmima,
naročito Propionibacterium acnes.
Kliničke varijante: Prvi klinički znaci oboljenja su
seboreja i komedoni (otvoreni i zatvoreni). Tokom
sledećih nekoliko meseci, javljaju se upalne promene,
koje se sastoje od papula i površno lokalizovanih
pustula, veličine do 5 mm. Mogu da se jave i dublje
lokalizovane upalne promene, kao što su nodulusi,
pustule veće od 5 mm i pseudociste. Posledica upalnih
promena je stvaranje ožiljaka, koje može biti udruženo
20
sa gubitkom kolagena, u vidu atrofičnih makularnih i
„icepick” ožiljaka, ili se, zbog izražene fibrozne reakcije
ispoljava u vidu hipertrofičnih ožiljaka.
Terapijski principi: S obzirom na multifaktorsku
patofiziologiju akni, lečenje se mora usmeriti protiv,
što je moguće više činilaca koji učestvuju u njihovom
nastajanju i prilagoditi kliničkoj slici.
Cilj terapije podrazumeva uglavnom kombinovanu
terapiju, a najvažnije je postizanje kliničkog
poboljšanja, sa što je manje moguće izraženim
ožiljavanjem i reziduama.
Neupalne akne: Koriste se topikalni lekovi koji deluju
antiseboroično, npr. spironolakton i antikomedogeno,
npr. retinoidi i azelaična kiselina.
Upalne akne: Za lečenje blažih i srednje teških oblika
upalnih akni, potrebno je primeniti benzoil-peroksid,
klindamicin, azelaičnu kiselinu. Za srednje teške
upalne oblike, koji zahvataju veće površine kože,
lečenje se sprovodi sistemskom primenom antibiotika,
najčešće tetraciklina, eritromicina i azitromicina.
Nodulo-cistične akne, kao i srednje teški oblici koji
ne daju zadovoljavajući odgovor na primenjenu
konvencionalnu lokalnu i sistemsku terapiju, akne sa
izraženim ožiljavanjem, kao i pacijenti sa psihološkim
problemima, predstavljaju indikaciju za sistemsku
primenu isotretinoina.
Zaključak: Lečenje se planira individualno, u odnosu
na kliničku sliku i težinu oboljenja, kao i psihološki
profil obolelog. Lečenje je dugotrajno i zahteva
obostranu predanost i istrajnost i obolelih i lekara.
Serbian Journal of Dermatology and Venereology 2010; (2)1: xx-xx
21
THE NOVI SAD DERMATOVENEREOLOGIC
MOULAGE COLLECTION,
CLINIC OF DERMATOVENEREOLOGY, CLINICAL CENTER OF VOJVODINA, NOVI SAD, SERBIA
VOJISLAV ŠIKOPARIJA, SCULPTOR DONATES HIS MOULAGES
TO THE FACULTY OF MEDICINE IN NOVI SAD, BELGRADE, 1964
CASE REPORT
Malignant transformation of a chronic leg ulcer: a case report
Kristina KOSTIĆ*, Tomislav MLADENOVIĆ, Radoš ZEČEVIĆ
Department of Dermatology and Venereology, Military Medical Academy, Belgrade
*Correspondence: Kristina KOSTIĆ, E-mail: [email protected]
UDC 616.5-006.6:611.98
Abstract
Squamous cell carcinoma (SCC) is a malignant tumor of epidermal keratinocytes which may arise de novo, or at
already affected skin areas of different etiology, including chronic vascular ulcers (CVUs). We present a 74-year-old
female patient, hospitalized in the Department of Dermatology, with venous ulceration of the lower right leg, 10x5 cm in
size, with well-demarcated edges, and the base covered with fibrin and granulation tissue. The ulceration appeared 7
years ago, while 3 years ago it spread rapidly with pain in the right lower leg. In the beginning, the patient was treated
with local and systemic antibiotic therapy. Later, hydrocoloid dressings and compressive bandages were applied, and
after that hyperoxygenation was performed in the hyperbaric chamber. Although the above-mentioned therapy was
applied correctly, it was not efficient. Since malignant alteration was suspected, two biopsies were taken and in both,
histopathologic analysis showed granulation tissue without dysplasia. The third biopsy, however, performed a month
after the second one, revealed a squamous cell carcinoma. After further investigations, amputation of the right lower
leg was suggested. Therefore, in cases with extended CVUs without no adequate therapeutical response during a
long period of time, malignant transformation should be considered, and multiple biopsies at various sites should be
performed.
L
ong-lasting chronic leg ulcers (CLUs) of vascular
origin are at increased risk for transformation
into carcinomas. Malignant transformations are
rare, and often misdiagnosed complications of CLU.
However, the most common among them are welldifferentiated squamous cell carcinomas (2). Clinical
sings of malignant CLU include abnormal granulation
tissue, the edges of the ulcer well differentiated from
the surrounding skin, failure of progress despite
accurate diagnosis and treatment, unusual pain
and abnormal bleedding. Malignancy in CLU is
confirmed by histopathology, taking multiple biopsies
from different sites of the ulcer (3). It is necessary
to determine the clinical stage of lesions, whereas
histopathological differentiation reveals the extention
of lesions, important for proper treatment.
Case report
We present a female patient, 74 years of age, admitted
to the Department of Dermatology and Venereology
of the Military Medical Academy with a lower leg
ulceration which appeared 7 years ago. The ulceration
increased in depth and width with years until it reached
10x5 cm in size, with intense pain, regardless of time
or activity. The patient had no history of diabetes,
or other chronic diseases, except for hypertension. It
started 3 years ago, and was under good control with
antihypertensive therapy. The ulceration was located
on the front side of the right lower leg, irregular
shaped, with hard edges, while the bottom was filled
with granulations and even a slight touch could cause
bleeding. The surrounding skin was unchanged, and
lymph nodes were not enlarged (Figure 1).
Laboratory findings showed a mild anemia,
while the other findings were within normal limits.
Ultrasonography of the lower extremities revealed
insufficiency of perforating venules in the distal third
of the right lower leg, without signs of deep venous
thrombosis, but degenerative changes were diagnosed
on the arteries. Chest radiography and abdominal
ultrasound findings were normal in the beginning,
and the patient was treated with local and systemic
antibiotic therapy. After that, hydrocolloid dressings
and compressive bandages were used, without success,
so hyperoxygenation in hyperbaric chamber was
performed. None of these therapeutic modalities
23
K. Kostić at. al
Malignant transformation of a chronic leg ulcer
Discussion:
Figure 1. The ulceration on the front side of the
right lower leg
were effective. Since the ulcer was refractory to
treatment, a malignant alteration was suspected. In
short period of time, two biopsies were taken and
both histopathological findings revealed granulation
tissue without dysplasia. During the following month,
conservative therapy (antibiotic, antiseptic and
compressive therapy) was continued, but it resulted
with increased granulation tissue formation at the
bottom and borders of the ulceration.
On the next admission, a sample was taken again
for cytologicae examination, and malignant cells were
found. The third biopsy was taken from the border of
the ulceration, and histopathological analysis revealed
a squamous cell carcinoma, grade III (Figure 2).
Radiography of the right lower leg showed incipient
osteolysis, but neither lymph node involvement, nor
visceral metastases were established by ultrasound.
There was no evidence of malignancy dissemination,
and the disease regressed to stage Ib. After consulting
plastic, vascular and orthopedic surgeons, amputation
of the right lower leg was recommended, and rejected
by the patient. She was dismissed with symptomatic
therapy.
24
SCC is the most common type of tumor arising from
a chronic leg ulcer (CLU). Malignant transformations
of chronic leg ulcers are mainly encountered in elderly
patients over 70 years of age, and more often in
females (female to male ratio: 2.5:1) (1).
In our patient, the ulceration appeared seven years
before the diagnosis of SCC was made. According to the
literature, SCC associated with chronic ucerations, the
above-mentioned period is not a long one. The study
of Combemale et all. performed in 2007 in France,
included 85 patients with malignant transformation
of CLU. In these patients the transformation lasted
27 years, on average (1). In our case report, the patient
presented with all clinical characteristics of malignant
transformation: abnormal granulation tissue, well
defined peripheral margins, protracted course and
spreading of the ulcer despite appropriate treatment,
unusual pain and abnormal bleeding. However, the
diagnosis could not be established after two biopsies.
Hanson et al. pointed to the difficulty of obtaining
histological confirmation, even in granulating forms,
and recommended (5), similar to Bardursson et al.,
multiple (up to five) biopsies at several sites of the
ulcer, estimating a 25% risk of false-negative results
upon a single biopsy (4).
Radiography revealed incipient osteolysis in
our patient, while there was neither lymph node
involvement, nor visceral metastases. In their study
Combemale et al. found that 41% of tumors invaded
Figure 2. Skin biopsy, exulcerated and infiltrative
keratinized squamous cell carcinoma (HE x 100)
CASE REPORT
the underlying bone, whereas lymph node involvement
and visceral metastases occurred rarely (9%) (1).
Histological differentiation is a major prognostic
factor. Tumors may be well, moderately or poorly
differentiated (6). Treatment depends on the clinical
stage of the disease. Amputation shoud be considered
for all tumors that are not well differentiated (6).
According to Baldursson et al. radiotherapy is
only palliative. In our patient, amputiation was
recommended as the best therapeutic option,
taking into consideration the size and depth of the
tumor invasion and grade III SCC, confirmed by
histopathological analysis, but it was rejected by the
patient.
Conclusion:
In cases of long term CVU and absence of adequate
therapeutic response, malignant transformation
should be considered and multiple biopsies at various
sites of the lesion should be performed.
References:
1. Combemale P, Bousquet M, Kanitakis J, Bernard P. Malignant
transformation of leg ulcers: a retrospective study of 85 cases. J
Eur Acad Dermatol Venereol 2007;21:935-41.
2. Baldursson B, Sigurgeirsson B. Venous leg ulcers and
squamous cell carcinoma: a large- scale epidemiological study.
Br J Dermatol 1995;133:571-4.
3. Yanh D, Morrisson BD, Vandongen YK, Sing A, Stacey M.
Malignancy in chronic leg ulcers. Med J Aust 1996;164:718-20.
4. Baldursson B, Hedblad MA, Beitner H, Lindelöf B. Squamous
cell carcinoma complicating chronic venous leg ulceration: a
study of the histopatology, course and survival in 25 patients, Br
J Dermatol 1999;140:1148-52.
5. Hanson C, Anderssom E. Malignant skin lesions on the leg
and feet at a dermatological leg ulcer clinic during five years.
Acta Derm Venereol (Stockh) 1997;78:147-8.
6. Motley R, Kersy P, Lawrence C. Multiprofessional guidelines
for the management of the patient with primary cutaneous
squamous cell carcinoma. Br J Dermatol 2002;146:18-25.
Maligna alteracija hronične venske ulceracije na podkolenici:
prikaz slučaja
Sažetak
Uvod: Planocelularni karcinom kože je maligni
tumor keratinocita koji može da se javi de novo ili na
već izmenjenoj koži različite etiologije, uključujući i
hroničnu vensku ulceraciju.
Prikaz slučaja: Bolesnica starosti 74 godine,
hospitalizovana u Klinici za kožne i polne bolesti, VMA
sa venskom ulceracijom desne potkolenice promera
10x5 cm, podrivenih i eleviranih ivica, dna prekrivenog
obilnim fibrinskim naslagama i granulacionim
tkivom. Ulceracija se pojavila pre 7 godina, a od pre
3 godine se izrazitije širila i produbljivala sa bolovima
u desnoj potkolenici. Uzet je isečak ivice ulceracije za
patohistološku analizu u dva navrata i oba puta viđeno
je granulaciono tkivo. Bolesnica je lečena ambulantno i u više navrata hospitalno različitom lokalnom
i antibiotskom terapijom, hidrokoloidnim pločama,
kompresivnim zavojima, oksigenom terapijom u
hiperbaričnoj komori bez zadovoljavajućeg efekta. Zbog
dalje sumnje na malignu alteraciju uzet je otisak rane
za citološku analizu i viđene su ćelije koje mogu da
odgovaraju planocelularnom karcinomu, što je tek trećom
biopsijom i dokazano, isptivanjima radi određivanja
stadijuma, utvrđeno je da je bolest u IB stadijumu. Uz
konsultaciju hirurga-plastičara, vaskularnog hirurga i
ortopeda, indikovana je amputacija desne potkolenice.
Zaključak: Ukoliko hronična ulceracija nema adekvatan
terapijski odgovor i ne zarasta uprkos terapiji,
neophodno je misliti na malignu alteraciju i učiniti
nekoliko sukcesivnih biopsija sa više različitih mesta
ulceracije radi PH analize.
25
B. Lalević-Vasić and M. Jovanović
Dermatovenereology in Serbia from 1919 - 1945-part IV/1
History of dermatology and venereology in Serbia – part IV/1:
Dermatovenereology in Serbia from 1919 – 1945
Bosiljka M. LALEVIĆ-VASIĆ1* and Marina JOVANOVIĆ2
Institute of Dermatology and Venereology, Clinical Center of Serbia, Belgrade, Serbia
Clinic of Dermatovenereology Diseases, Clinical Center of Vojvodina, Novi Sad, Serbia
*Correspondence: Bosiljka LALEVIĆ-VASIĆ, E-mail: [email protected]
1
2
UDC 616.5:614.2(091)(497.11)”1919/1945”
UDC 616.97:614.2(091)(497.11)”1919/1945”
Abstract
After the First World War, Serbia was ravaged and in ruins, whereas the Health Care Service was destroyed.
Organization and reorganization of the Health Care Service started with a fight against the spread of infectious diseases.
Foundation of specialized health institutions was among the first tasks. As early as 1920, an Outpatient Service for
Skin and Venereal Diseases was established and managed by Prof. Đorđe Đorđević. In 1922, after he was appointed
as Associate Professor at the newly established Faculty of Medicine in Belgrade, he founded a Clinic for Skin and
Venereal Diseases, and acted as its first director. In 1928, a Municipal Outpatient Clinic for Skin and Venereal Diseases
was founded, whereas in 1938 a modern organization of the Service was established in a new building. After a break
during the I World War, the Dermatovenereology Department of the General Military Hospital in Belgrade, founded in
1909, continued working until the Second World War. In Novi Sad, the City Hospital was founded in 1909, including a
Dermatovenereology Department. After the First World War, in 1921, Dr. Jovan Nenadović founded a Department of Skin
and Venereal Diseases (100 beds) in the General Public Hospital, as well as, an independent Public Outpatient Clinic
for free-of-charge treatment of patients with venereal diseases. In Niš, the first Organization Unit for Venereal Diseases
was founded in 1912, but the Department of Venereal Diseases was founded in 1921, and it was managed by Dr.
Petar Davidović, while in 1927 a Department of Skin and Venereal Diseases was established within the General Public
Hospital. In 1920, a Dermatovenereology Department of the Military Hospital in Niš was established. Apart from these,
as early as 1921, there was a total of 7 Outpatient Clinics in Serbia, and in 1923 there were 14 venereal departments,
and 1 dermatovenereology department.
A
fter the First World War, the Kingdom of Serbs,
Croats and Slovenes was proclaimed in 1918, as
well as the first Ministry of Public Health (MPH).
Thus, the whole enlarged country was integrated into
a unique system of health care delivery, although the
initial positions of certain parts were quite different.
The seven-year war (1912 – 1918), occupation and
epidemics of infectious diseases led to a massive loss
of lives and medical personnel in Serbia (1). Out of
nearly three million inhabitants of Serbia before the
First World War, over 1.200.000 people lost their lives
(2), including 35% of physicians (1). The country was
ravaged and in ruins (1, 3), whereas the Health Care
Service was destroyed. Infectious and venereal diseases
spread, and it was necessary to start organization
and reorganization of the sanitary service (1). Again,
26
it meant starting from scratch, in somewhat better
circumstances than earlier, because some habits and
laws have been preserved, and the health care service
had had a certain tradition.
Legislation and Organization of the
Dermatovenereology Service
Shortly after the war, proper legal regulations were
brought, but they were replaced in 1921 by the Law
on the Foundation of Special Institutions for Infectious
Diseases and Free-of Charge Health Care Service (1,
2). Based on this Law, the MPH was responsible for
the: detection, eradication and treatment of acute and
chronic infectious diseases, keeping strict records of
patients and for health education of the population
(1). The Law on the Eradication of Infectious Diseases,
HISTORY OF MEDICINE
passed in 1930, included the following guidelines
for venereology: foundation of institutions for freeof-charge treatment; employment of professionally
educated physicians; foundation of hospital
departments for venereal diseases; units for prevention
of venereal diseases; institutions for the treatment of
children with congenital syphilis; mobile outpatient
services; forced treatment, and taking special measures
in counties where more than 5% of population
were infected by syphilis. Reporting diseases was
mandatory in cases where spread of infection was
anticipated. In 1931 and 1934, Laws on Eradication
of Endemic Syphilis (1) and of Venereal Diseases were
passed, respectively (4). Skin diseases were covered by
General Legislation.
Three basic problems were recognized in the
organization of public health care: insufficient number
of hospitals and physicians, and almost complete
lack of bacteriological laboratories (1). The first two
problems were directly related to dermatovenereology.
Health Institutions
The Outpatient Service for Skin and Venereal Diseases
(OSSVDs) was founded by a special regulation of the
MPH in Belgrade in 1920, since it was the Center
for organization of Sanitary Services in Serbia (1).
Firstly it was situated in Dečanska Street, then in
Vidinska Street (today George Washington street),
which remained recognized as a location of the first
dermatovenereology institutions in Belgrade, but also
by a great number of brothels, which were there before
and after the First World War (5). Dr. Đorđe Đorđević
(Figure 1) was the Head of the OSSVDs, and Dr.
Sima Ilić (Figure 2), was the dermatovenereologistpractitioner (6). Both of them were very important for
the development of the Serbian dermatovenereology.
The Service provided a temporary residence to the
newly founded Clinic for Skin and Venereal Diseases
(see below). When the Clinic was moved in 1925, the
OSSVDs continued working as the institution of the
MPH, and Dr. Sima Ilić was the Head of the Service
(6).
The Clinic for Skin and Venereal Diseases (CSVDs)
was founded in 1922, when dr Đorđević was appointed
as Associate Professor at the newly established Faculty
of Medicine in Belgrade (1920) (7). The Clinic had no
capacities for in-patients (8), but all other health and
Figure 1. Prof. Dr. Đorđe Đorđević
educational activities were exercised at the OSSVDs,
based on the agreement between the Faculty of
Medicine and the MPH (6). Till 1932, the CSVDs has
been moved two more times into private residences,
unfortunately always in inadequate premises. Hospital
departments were founded in 1925, whereas in 1932,
the CSVDs was moved to the facilities of the Institute
of Anatomy, which had previously been used by the
(cancelled) Clinic of Applied Anatomy (6) (Figure 3).
The working conditions were somewhat better, and
apart from hospital departments and laboratories, in
1935 the Clinic possessed a library with 700 books
and 450 journals, as well as a moulage collection of
400 exhibits (7). Apart from this, in 1935 a Specialized
Outpatient Service was opened for treatment of
27
Figure 2. Prof. Dr. Sima Ilić
students (9). During the Second World War, the
occupation authorities took possession of the Clinic
with the entire inventory, so that only the Outpatient
Service continued working. After the Germans had
left in 1944, part of the library and the moulage
collection remained behind (10). The first Head of the
CSVDs was Professor Đorđe Đorđević (1922 – 1935),
followed by Professor M. Kićevac (1935 – 1940) (7),
and Dr. Sava Bugarski (1940 – 1944) (6,11).
The Dermatovenereology Departments of the
General Public Hospital (GPH), founded in Belgrade
at the end of the XIX century (see part III/1), the first
dermatovenereology departments for in-patients in
Serbia, continued working after the First World War.
The Municipal Outpatient Clinic for Skin
and Venereal Diseases in Belgrade was founded on
September 15, 1928. During the following ten-year
period, it was housed in inadequate private facilities,
with small and disorganized settings (Figure 4).
When the economic crisis ended in the 1930s, a new
building was built in 1938 in Vidinska Street (17,
George Washington Street), and it was called the City
Outpatient Clinic, today City Department of Skin and
Venereal Diseases. It was a modern building and it
was the first institution of its kind in Central Europe
(Figure 5). The Head of the Institution was Dr. Jovan
Spasojević who worked with Dr. Mihailo Gačić, both
dermatovenereologists. Its significance can easily be
seen from the following data: during 1928, a total
of 1.072 patients were examined, in 1929, 15.217
patients, and in 1937, 51.194 patients had undergone
examination (5).
The Department of Skin and Venereal Diseases (100
beds) of the General Public Hospital (GPH) (Figure 6),
Figure 3. The Institute of Anatomy in Belgrade, a temporary residence of the Clinic for
Skin and Venereal Diseases in 1932 (indicated by an arrow)
28
HISTORY OF MEDICINE
Figure 4. The Municipal Outpatient Clinic for Skin
and Venereal Diseases in Belgrade
Figure 5. The City Outpatient Clinic for Skin and
Venereal Diseases in Belgrade
and the independent Public Outpatient Clinic for freeof-charge treatment of patients with venereal diseases
in Novi Sad, were founded in 1921, by Dr. Jovan
Nenadović, the first Serbian dermatovenereologist in
Vojvodina. He was the director of both institutions
(12). We must also note that in 1909, the City
Hospital with a Dermatovenereology Department was
founded (13), but after the First World War there
was no place for treatment of patients with skin and
venereal diseases (12). Apart from that, an AntiVenereal Outpatient Department was founded in 1925
(13). Further development of dermatovenereology
in Vojvodina started with these institutions with
close cooperation with the Belgrade Dermatology
School. Dermatovenereologists, who took part in the
development of dermatovenereology, and in the work
of institutions of that time, were also members of
the Dermatovenereology Section of the Serbian Medical
Association.
The first Organization Unit for Venereal Diseases
in Niš was founded in 1912, and in 1920 it was
moved into the bungalows of the City Hospital. The
Department for Venereal Diseases with an Outpatient
facility outside the Hospital circle was founded in
1921 and it was managed by Dr. Petar Davidović.
A Department for Skin and Venereal Diseases of the
GPH in Niš was opened in 1927. Its director was Dr.
Petar Zurin, a dermatovenereologist (1, 14). After the
foundation of the Faculty of Medicine in Niš (1960) it
had become a teaching hospital for medical students
(14) (Figure 7).
In 1921, at the initiative of Prof. Đ. Đorđević,
Serbia had complete outpatient health care centers
in Niš, Petrovac, Užice, Boljevac County, Subotica,
Veliki Bečkerek (Zrenjanin) and Mitrovica (15).
As soon as 1923, general hospitals had 14 venereal
departments and 1 dermatovenereology department,
Figure 6. The General Public Hospital in Novi Sad
with the Department of Skin and Venereal Diseases
(Archive of Vojvodina)
29
Figure 7. The General Public Hospital in Niš,
the present Clinic for Skin and Venereal Diseases
(indicated by an arrow)
in Subotica (16). It is noticeable that these departments
were called “venereal”, just as the physicians were
called “venereologists” (1), pointing once again
to the fact that venereal diseases were still a major
dermatovenereology problem.
The Dermatovenereology Department of the
General Military Hospital in Belgrade, founded in
1909 (see part III/1), worked until the First World
War, when the General Military Hospital, under the
Austrian occupation, became “Das K. und K Reservspital
Brško” (17). After the war, the Department continued
working till the beginning of the Second World War.
Figure 9. The Military Hospital in Niš with the
Dermatovenereology Department
From 1941 to 1944, the occupation authorities once
again used the General Military Hospital for their
purposes (18). After the war, it continued working
as the Main Military Hospital, moreover, the,
Dermatovenereology Department continued working
as well (19) (Figure 8).
After the First World War, in 1920, new
departments were founded in the Military Hospital
in Niš (Army Military Hospital for the territory of
Moravska military district) (Figure 9), including a
Dermatovenereology Department (20).
The first hospital for the treatment of syphilis in
Serbia was founded in 1851 in Knjaževac (see part II),
but during time it was transformed into the County
General Hospital (21). With the archive destroyed,
there is no evidence of its work, but it is apparent
that patients with syphilis prevailed, because it is well
known that at the beginning of the 1950’s, this was
the most outspread and best known area with endemic
syphilis in Serbia (22).
References
Figure 8. The Main Military Hospital in Belgrade with
the Dermatovenereology Department
30
1.Milovanović V. editor. Medicinski godišnjak Kraljevine
Jugoslavije (Annual Medical Report of the Kingdom of
Yugoslavia). Beograd Jugoreklam K.D; 1933.
2.Djokić D, Dovijanić P. Osamdeset godina u službi zdravlja
naroda. 2. izd. (80th Anniversary of the Public Health Service,
2nd ed). Beograd: Institut za zaštitu zdravlja Srbije “Dr Milan
Jovanović Batut”, Medicinski fakultet u Beogradu, Univerzitet
u Beogradu; 2000.
3. Davidović U. Dvadeset godina Opštine beogradske (20th
Anniversary of Belgrade Municipality). Beogr Opšt Nov
1939;57(1-2):7-14.
4. Zorko T. Ženska prostitucija u Zagrebu 1899. i 1934.godine
HISTORY OF MEDICINE
(Female prostitution in Zagreb in 1899 and 1934). Časopis
Suvrem Pov 2006;38(1):223-41.
5. Kićevac M. Gradska poliklinika za kožne i venerične bolesti
(City Outpatient Clinic for Skin and Venereal Diseases). Beogr
Opšt Nov 1938;56(3):215-7.
6. Kićevac M. Klinika za kožne i venerične bolesti (Clinic for
skin and Venereal Diseases). U: Medicinski fakultet Univerziteta
u Beogradu 1920-1935. Beograd: Medicinski fakultet; 1935. p.
125-31.
7. Stefanović S. et al. editors. 50 godina Medicinskog fakulteta
Univerziteta u Beogradu 1920-1970. (50th Anniversary of the
School of Medicine of the Belgrade University – 1920 – 1970).
Beograd: Galenika; 1970.
8. Pregled predavanja za zimski semestar 1924/1925 godine;
Univerzitetski kalendar (The Winter Curriculum for the
academic years 1924/1925; University Calendar). Beograd:
Univerzitet u Beogradu; 1924/1925.
9. Univerzitet u Beogradu 44 (Belgrade University 44). Beograd:
Publikacija Rektorata; 1935/1936.
10. Izveštaj Medicinskog fakulteta, nezaveden i nedatiran akt,
Arhiv Srbije (Report of the School of Medicine, unrecorded and
undated publication, Archive of Serbia).
11. Pregled predavanja za zimski semestar 1940/1941.godine
(The Winter Curriculum for the academic years 1940/1941).
Beograd: Univerzitet u Beogradu; 1940/1941.
12. Pedesetogodišnjica lekarskog i kulturnog rada dr Jovana
Nenadovića (50th Anniversary of the health and cultural work of
Dr. Jovan Nenadović). Med Pregl 1951;(9-10):1-3.
13. NN. Razvoj medicine u Novom Sadu (Progress of medicine
in Novi Sad). U: Budakov P, Pejin D, editors. Univerzitet
u Novom Sadu, Medicinski fakultet Novi Sad, 1960-2000:
Medicinski fakultet; 2000. p. 8-15.
14. Krstić S. 80 godina službe i 20 godina Klinike za kožne i
polne bolesti u Nišu (80th Anniversary of the Service and 20th
Anniversary of the Clinic for Skin and Venereal Diseases in Niš).
Niš: Univerzitetski klinički centar OJ Klinike za kožne i polne
bolesti;1991.
15. Djordjević Dj. Izveštaj o radu Ambulante za kožne i
venerične bolesti u Beogradu; Prilog “Glasniku Ministarstva
Narodnog Zdravlja” (Work report of the Outpatient Clinic for
Skin and Venereal Diseases in Belgrade; Addition to the “Journal
of the Ministry of Public Health”). Beograd; 1921:1-35.
16. Popović DG. O bolnicama (About Hospitals). Glasnik
Ministarstva Narodnog Zdravlja. Vanredno izdanje. Beograd;
1923:3-162.
17. Stojiljković MP, Zeljković J, Tadić V. Iz istorije
Vojnomedicinske akademije: I Vojne bolnice u Beogradu od
1836. do 1938. godine (Out of the history of the Military
Medical Academy: I Military Hospitals in Belgrade from 1836
to 1938). Vojnosanit Pregl 2002;59 (3):329-33.
18. Špirić Ž, Preradović M, Zeljković J. Iz istorije srpske i
jugoslovenske vojne psihijatrije: Nastanak i razvoj Klinike za
psihijatriju Vojnomedicinske akademije od 1932. do 2002.
godine. (Out of the history of Serbian and Yugoslav military
psychiatry: Foundation and progress of the Clinic of Psychiatry
of the Military Medical Academy from 1932 to 2002).
Vojnosanit Pregl 2002;59(6):681-7.
19. Dinić MŽ, Kandolf-Sekulović L, Zečević RD. Sto godina
dermatovenerologije u Vojsci Srbije (A hundred years of
dermatovenereology in the Serbian Army). Vojnosanit. Pregl.
2010; 67(1): 73-6
20. Vojna bolnica Niš (Military Hospital in Niš). Wikipedia
(cited in December, 2009). Available from: http: // sr.wikipedia.
org/sr-el.
21. Ivanović Šakabenta D. Sto pedeset godina bolnice u
Knjaževcu 1851-2001. (150th Anniversary of the Hospital
in Knjaževac: 1851 – 2001). Knjaževac: Zdravstveni centar
Knjaževac; 2001.
22. Ilić S, Ignjatović B. Endemski sifilis u Srbiji; Savremena
akcija na njegovom suzbijanju
(Endemic Syphilis in Serbia; An Eradication Campaign).
Beograd: Biblioteka Higijenskog instituta NR Srbije; 1957.
Abbreviations
CSVDs – Clinic for Skin and Venereal Diseases
GPH – General Public Hospital
MPH – Ministry of Public Health
OSSVDs – Outpatient Service for Skin and Venereal Diseases
Acknowledgement
With great pleasure, we acknowledge our gratitude to
Dr. Simon Dragović and Prof. Dr. Snežana Veljković.
We also wish to acknowledge our gratitude to Prof. Dr.
Branislav Filipović, Prim. Dr. Aleksandar Adamović
and Assistant Prof. Dr. Lidija Kandolf-Sekulović, for
their assistance in gathering valuable photographs.
31
REPORT
A report on the 11th International Union against Sexually
Transmitted Infections World
Congress
T
he International Union against Sexually
Transmitted Infections (IUSTIs) was founded in
1923, and it is organized on both global and regional
basis. It is the oldest international organisation with
the objective of fostering international cooperation in
the control of sexually transmitted infections (STIs),
including HIV/AIDS. IUSTIs is concerned with the
medical, scientific, social and epidemilogical aspects
of STIs and their control. It is an Official NonGovernment Organization in Consultative Status with
the World Health Organization.
The 11th IUSTIs World Congress took place in
Cape Town, South Africa, from 9th to 12th Novemeber
2009. This was the first IUSTIs meeting in Africa,
which has the highest burden of HIV infection in the
world, whereas STIs still play an important role in
fuelling the on-going transmission.
During the Congress, there were 7 plenary
lectures, 44 symposia in 17 topic symposia, 48 oral
presentations and 139 posters.
The plenary sessions covered rapid diagnostic tests
for STIs, prevention of mother to child transmission
of HIV, biological drivers of the HIV epidemic, sexual
networks, male circumcision, HIV vaccines, the use of
information technology in novel ways to improve STIs/
HIV clinical practice, STIs bacterial typing, updates in
STIs, human papilloma viruses (HPV) vaccination and
HPV clinical disease, STIs treatment as a component of
HIV prevention, and finally, IUSTIs global challenges.
STIs represent a major health problem in both
developed and developing countries, reflected by the
estimated 300 milion new cases occurring worldwide
every year. Although a decline in STIs has been observed
since the 1950s, in many countries an increase has been
reported during the last few years, especially in syphilis,
gonorrhea and some viral infections including HIV. At
32
Figure 1. Prof. Dr. Skerlev from Zagreb and
Dr. Zoran Golušin from Novi Sad during
the Congress in Cape Town
present, there are drugs which can eradicate bacterial,
protozoal and ectoparasitic infections. However,
challenges remain in countering genital pathogens
even where antibiotics are available, with the increasing
incidence of antibacterial resistance in gonococci.
High levels of resistance in gonococci especially
against quinolones has now become a worldwide
problem and reflects the ability of micro-organisms to
escape antibacterial strategies.
The major impact of STIs on public health today
derives from viral rather than bacterial infections, and
many viral infections still represent a major therapeutic
challenge. Hepatitis B and AIDS are a substantial
problem in Western Europe and the USA, but represent
devastating epidemics in Central and South Africa,
certain parts of Asia and Eastern Europe. Antiviral
resistance is an ongoing and increasing problem in the
treatment of HIV infected individuals.
Pre-exposure vaccination against hepatitis B is
recommended for individuals at risk, but vaccination
strategies may fail because of the high costs in developing
countries and public resistance against vaccination in general.
It has been known that high risk genotypes of
REPORT
HPV carry the risk of malignancy and lead to invasive
carcinoma of the genital tract in women and men. The
results of HPV vaccination are promising and give hope
that genital cancer can be reduced or even eradicated by
large scale vaccination programs.
Two posters from Serbia were presented: „Epidemiological Characteristics of Syphilis in Vojvodina
in the Last Three Decades“ by Zoran Golušin,
Slobodan Stojanović, Siniša Tasić, Zoran Nedić and
„Condylomata acuminata and Buschke-Lowenstein
tumor“ by Zoran Nedić and Zoran Golušin.
Zoran GOLUŠIN
Clinic of Dermatovenereology Diseases
Clinical Center of Vojvodina, Novi Sad, Serbia
*Correspondence: Zoran GOLUŠIN
E-mail: [email protected]
33
Serbian Journal of Dermatology and Venereology 2010; 2 (1)
34
FORTHCOMING EVENTS
FORTHCOMING EVENTS
Dermatology and Venereology Events 2010
DATE
MEETINGS, CONGRESSES,
SYMPOSIA
ABSTRACT
SUBMISSION
DEADLINE
7th World Congress of The
30 November,
18-23 March, 2010 International Academy of Cosmetic
2009
Dermatology (IACD), Cairo, Egypt
Hair and Scalp Diseases in Clinical
Under
26-28 March, 2010 Practice. Course and Symposium,
construction
Warsaw, Poland
th
13
World Congress on Cancers of the 15 February,
7-10 April, 2010
Skin, Madrid, Spain
2010
8-11 April, 2010 Winter Academy Dermatology, III Congress 31 January,
- St. Moritz-Pontresina, Switzerland
2010
World Dermatology & Laser
30 November,
13-15 April, 2010 Dubai
Conference & Exhibition, Dubai, UAE
2009
7th EADV Spring Symposium, Cavtat,
10 January,
Croatia
2010
10th ESPD (European Society for
14 December,
20-22 May, 2010 Pediatric Dermatology) Congress,
2009
Lausanne, Switzerland
Scientific meeting ”Diseases of the oral mucosa No abstract
- what is new? Academy of Medical Sciences
11 June, 2010
of theSerbian Medical Society, Belgrade, Serbia submission
th
28 February,
16-19 June, 2010 6 Congress of the European Association
of Dermatologic Oncology, Athens, Greece
2010
13-16 May, 2010
1-4 July, 2010
Congress of the Psoriasis International
Network, Paris, France
15 February,
2010
MORE INFORMATION AT
www.cairoderma.com
www.spederm.eu
www.wccs2010.com
www.winteracademy.net
www.dubaiderma.com
www.eadvcavtat2010.com
www.espd2010.com
www.sld.org.rs
www.eado2010.org
www.pso2010.com
1st International Summit for Nail
15 March, 2010 www.erasmus.gr/en/congresses/athens
Diseases, Athens, Greece
New Trends in Allergy VII & 6th Georg
22-24 July, 2010 Rajka Symposium, International Symposium 31 March, 2010
www.new-trends-allergy.de
on Atopic Dermatitis, Munich, Germany
16th Meeting of the European Society
31 May,
www.registration.hinxton.wellcome.ac.uk
4-7 September, 2010 for Pigment Cell Research, Hinxton
2010
Cambridge, UK
th
Annual ESDR Meeting (European
14 May,
9-11 September, 40
Society for Dermatological Research),
www.esdr2010.org
2010
2010
Helsinki, Finland
2-4 July, 2010
15-18 September, 10th Congress of the European Society of
2010
Contact Dermatitis, Strasbourg, France
March,
2010
6-10 October, 2010 19th EADV Congress Gothenburg, Sweden 3 March, 2010
XXXI Symposium of The International Society
21-23 October, 2010 of Dermatopathology, Barcelona, Spain
29 October – 01
November, 2010
10th ADI (Ionic Dermatological Association)
International Congress, Floriana, Malta
1st World Congress on Controversies
4-7 November, 2010 in Plastic Surgery and Dermatology,
Barcelona, Spain
www.escd-gerda2010.com
www.eadvgothenburg2010.org
Under
construction
www.isdpbarcelona2010.net
27 August,
2010
www.malta2010.net
4 August, 2010
www.comtecmed.com/coplasdy/2010
Prepared by: Dr. Tatjana Roš, Clinic of Dermatovenereology Diseases, Clinical Center of Vojvodina, Novi Sad, Serbia
35
AUTHOR GUIDELINES
AUTHOR GUIDELINES
Serbian Journal of Dermatology and Venereology is a
journal of the Serbian Association of Dermatologists and
Venereologists. The journal is published in English, but
abstracts will also be published in Serbian language.
The journal is published quarterly, and intended
to provide rapid publication of papers in the field
of dermatology and venereology. Manuscripts are
welcome from all countries in the following categories:
editorials, original studies, review articles, professional
articles, case reports, and history of medicine.
Categories of Manuscripts
1. Editorials (limited to 5 pages) generally provide
commentary and analyses concerning topics of current
interest in the field of dermatology and venereology.
Editorials are commonly written by one author, by
invitation.
2. Original studies (limited to 12 pages) should
contain innovative research, supported by randomized
trials, diagnostic tests, outcome studies, cost-effectiveness
analysis and surveys with high response rate.
3. Review articles (limited to 10 pages) should provide
systemic critical assessment of literature and other data
sources.
4. Professional articles (limited to 8 pages) should
provide a link between the theory and practice, as well as
detailed discussion or medical research and practice.
5. Case reports (limited to 6 pages) should be new,
interesting and rare cases with clinical significance.
6. History of medicine (limited to 10 pages) articles
should be concerned with all aspects of health, illness and
medical treatment in the past.
The journal also publishes book reviews, congress
reports, as well as reports on local and international
activities, editorial board announcements, letters to the
editor, novelties in medicine, questions and answers, and
“In Memoriam”. All submitted manuscripts will undergo
review by the editor-in-chief, blind review by members of
the manuscript review panel or members of the Editorial
Board. Manuscripts submitted to this journal must not be
under simultaneous consideration by any other publisher.
Any materials submitted will NOT BE RETURNED to
the author/s.
36
All manuscripts should be submitted to the Editor
in Chief: Prof. Dr. Marina Jovanović, Clinic of
Dermatovenereologic Diseases, Clinical Center of
Vojvodina, Hajduk Veljkova 1-3, Novi Sad, Serbia, by
mail to: [email protected].
Manuscripts for submission must be prepared
according to the guidelines adopted by the International
Committee of Medical Journal Editors (www.icmje.
org). Please consult the latest version of the Uniform
Requirements for Manuscripts Submitted to Biomedical
Journals.
1.Manuscript Preparation Guidelines
The manuscript should be written in English,
typed in double spacing throughout on A4 paper, on
one side only; Use Times New Roman, font size 12,
with 30 lines and 60 characters per line. Articles must
be written clearly, concisely and in correct English.
Accepted manuscripts in need of editing will be
returned after editing to the corresponding author for
approval. When preparing their manuscripts, authors
should follow the instructions given in the Categories of
Manuscript: the number of pages is limited (including
tables, figures, graphs, pictures and so on to 4 (four)),
and all the pages must be numbered at the bottom
center of the page.
For manuscript preparation, please follow these
instructions:
1.1. Title page
The title page should include the following information:
- The title of the article, which should be informative,
without abbreviations and as short as
possible;
- A running title (limited to 30 characters);
- Authors’ names and institutional affiliations;
- The name, mailing address, telephone and fax
numbers, and email of the corresponding author responsible
for correspondence about the manuscript. Furthermore,
authors may use a footnote for acknowledgements,
information and so on.
1.2. Abstracts
A structured abstract in English (limited to 150
words) should follow the title page. The abstract should
AUTHOR GUIDELINES
provide the context or background for the study, as well as
the purpose, basic procedures, main findings and principal
conclusions. Authors should avoid using abbreviations.
- An abstract in Serbian language, (limited to 150
words) should follow the second page. It should contain a
briefing on the purpose of the study, methods, results and
conclusions, and should not contain abbreviations.
1.3. A list of abbreviations
Use only standard abbreviations, because use of nonstandard abbreviations can be confusing to readers.
Avoid abbreviations in the title, abstract and in the
conclusion. A list of abbreviations and full terms for
which they stand for should be provided on a separate
page. All measurements of length, height, weight, and
volume should be reported in the metric units of the
International System of Units – SI, available at http://
www.bipm.fr/en/si/.
1.4. Cover Letter
Manuscripts must be accompanied by a cover letter,
which should include a date of submission, statement
that the manuscript has been read and approved by all
the authors and that the authorship requirements have
been met. It should also include the name, address, and
telephone number of the corresponding author, who is
responsible for communicating with other authors about
revisions and final approval of the proofs. The original
copy of the cover letter, signed by all authors, should be
enclosed with the manuscript.
- Figures should be submitted in a separate
file, not included in the manuscript document. Cite
figures consecutively, as they appear in the text, with
Arabic numbers (Fig. 1, Fig. 2, Fig. 3, etc.). Each
figure must be assigned a title, as well as a legend.
Legends should appear on a separate page, not with
each figure. The Legend Page is to be numbered
in sequence after the last page of the references list.
Figures should be professionally drawn, as sharp
black-and-white or color photographs. If photographs
of persons are used, either the subjects must not be
identifiable, or their pictures must be accompanied by
written permission to use them.
3. References
References in the text, tables and legends should be
identified by Arabic numerals in parentheses. Number
references consecutively in the order in which they are
first mentioned in the text. The Vancouver System of
referencing should be used. List each author’s last name
and initials; full first names are not included. List all
authors, but if the number exceeds six, give the first
six followed by „et al.” National journals, which are
not indexed in Index Medicus, should be abbreviated
according to the style in the List of Abbreviated Titles
of Yugoslav Serial Publications available on http://
vbsw.vbs.rs. For further information please visit www.
ICMJE.org.
Tables should capture information concisely and precisely.
Including data in tables, rather than in the text, reduces
the length of the article itself.
4. Additional information
Accepted manuscripts are edited and returned to the
corresponding author for approval. Then a final version
of the manuscript will be requested in a defined period of
time. Authors will be notified of acceptance or rejection by
email, within approximately 4 weeks after submission.
- Submit tables in separate files, not included in the
manuscript. Tables are to be double spaced and numbered
sequentially, with Arabic numbers (Table 1, Table 2, etc.),
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Put all explanatory matter in footnotes, including any
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For further information please contact the Editorial
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2. Tables and illustrations
- Open access: Every article published in the
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37
Serbian Journal of Dermatology and Venereology 2010; 2 (1)
CIP – Каталогизација у публикацији
Народна библиотека Србије, Београд
616.5(497.11)
SERBIAN Journal of Dermatology and
Venerology / editor-in-chief Marina
Jovanović. - Vol. 1, no. 1 (january 2009). - Belgrade (Pasterova 2) : The Sebian
Association of Dermatovenereologists, 2009(Beograd : Zlatni presek). - 30 cm
Tromesečno
ISSN 1821-0902 = Serbian Journal of
Dermatology and Venerology
COBISS.SR-ID 156525836
38
Serbian Journal of Dermatology and Venereology 2010; (2)1: xx-xx
Cover figure: Christ Healing Ten Lepers, Christ’s Miracles, XIVth century, The monastery Visoki Dečani, Serbia, Kosovo
Published by the
Serbian Association of Dermatovenereologists

No. 1, March 2010

Transcription

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